Substituted oxygen alicyclic compounds, including methods for synthesis thereof

ABSTRACT

The invention provides new methods for preparation of cyclic oxygen compounds, including 2,5-disubstituted tetrahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. The invention also provides new cyclic oxygen compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds.

The present application is a continuation of U.S. application Ser. No.09/347,113, filed on Jul. 2, 1999 now U.S. Pat. No. 6,306,895, whichclaims the benefit of U.S. provisional application No. 60/091,694, filedJul. 3, 1998, which is incorporated herein by reference in its entirety.

BACKGROUND

1. Field of the Invention

The present invention provides new methods for preparation of variousoxygen ring compounds (oxygen as an alicyclic ring member) including2,5-disubstituted-tetrahydrofurans, 2,6-disubstituted tetrahydropyrans,2,7-disubstituted oxepanes and 2,8-oxocanes. The invention furtherprovides novel compounds and pharmaceutical compositions and therapeuticmethods that comprise such compounds.

2. Background

Leukotrienes are recognized potent local mediators, playing asignificant role in inflammatory and allegeric responses, includingarthritis, asthma, psoriasis and thrombotic disease. Leukotrienes areproduced by the oxidation of arachidonic acid by lipoxygenase. Moreparticularly, arachidonic acid is oxidized by 5-lipooxygenase to thehydroperoxide 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), that isconverted to leukotriene A₄, that in turn can be converted toleukotriene B₄, C₄, or D₄. The slow-reacting substance of anaphylaxis isnow known to be a mixture of leukotrienes C₄, D₄ and E₄, all of whichare potent bronchoconstrictors.

Efforts have been made to identify receptor antagonists or inhibitors ofleukotriene biosynthesis, to prevent or minimize pathogenic inflammatoryresponses mediated by leukotrienes.

For example, European Patent Application Nos. 901171171.0 and901170171.0 report indole, benzofuran, and benzothiophene lipoxygenaseinhibiting compounds.

Various 2,5-disubstituted tetrahydrofurans have exhibited significantbiological activity, including as lipoxygenase inhibitors. See U.S. Pat.Nos. 5,703,093; 5,681,966; 5,648,486; 5,434,151; and 5,358,938.

While such compounds are highly useful therapeutic agents, currentmethods for synthesis of least some of the compounds require lengthyroutes, and reagents and protocols that are less preferred in largerscale operations, such as to produce kilogram quantities.

It thus would be desirable to have improved methods to substitutedtetrahydrofurans and other cyclic oxygen compounds, particularly newsyntheses that facilitate larger scale production of such compounds.

SUMMARY OF THE INVENTION

We have now found new methods for preparation of cyclic oxygencompounds, including 2,5-disubstituted tetrahydrofurans,2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and2,8-oxocanes. These methods utilize reagents and synthetic protocolsthat facilitate large scale manufacture, and provide increased yieldsrelative to prior approaches.

The methods of the invention are suitable for preparation of a varietyof cyclic oxygen-containing compounds (i.e., alicyclic compounds havingan oxygen ring member), including compounds of the following Formula I:

wherein Ar is optionally substituted carbocyclic aryl or optionallysubstituted heteroaryl;

each R¹, X and Y is independently hydrogen or a non-hydrogen substituentsuch as halogen, hydroxyl, optionally substituted alkyl preferablyhaving from 1 to about 20 carbon atoms, optionally substituted alkenylpreferably having from 2 to about 20 carbon atoms, optionallysubstituted alkynyl preferably having from 2 to about 20 carbon atoms,optionally substituted alkoxy preferably having from 1 to about 20carbon atoms, optionally substituted alkylthio preferably having from 1to about 20 carbon atoms, optionally substituted alkylsulfinylpreferably having from 1 to about 20 carbon atoms, optionallysubstituted alkylsulfonyl preferably having from 1 to about 20 carbonatoms, optionally substituted aminoalkyl preferably having from 1 toabout 20 carbon atoms, optionally substituted alkanoyl preferably havingfrom 1 to about 20 carbon atoms, optionally substituted carbocyclic arylhaving at least about 6 ring carbons, or substituted or unsubstitutedaralkyl having at least about 6 ring carbons, and the like;

Z is a chemical bond, optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkylene, optionallysubstituted heteroalkylene, optionally substituted heteroalkenylene,optionally substituted heteroalkylene, or a hetero atom such as O, S,S(O), S(O)₂, or NR¹ wherein R¹ is the same as defined immediately above;

n is an integer from 1 to 11, and preferably is 1 to 9, more preferably1 to 7;

p is an integer from 0 (where the α and β ring positions are fullyhydrogen-substituted) to 4; and pharmaceutically acceptable saltsthereof.

The methods of the invention are particularly suitable for synthesis ofsubstituted tetrahydrofurans, including compounds of the followingFormula II:

wherein Ar is optionally substituted aryl or heteroaryl;

m is 0 or 1; n is 1-6;

W is —AN(OM)C(O)N(R³)R⁴, —N(OM)C(O)N(R³)R⁴, —AN(R³)C(O)N(OM)R⁴,—N(R³)C(O)N(OM)R⁴, —AN(OM)C(O)R⁴, —N(OM)C(O)R⁴, —AC(O)N(OM)R⁴,—C(O)N(OM)R⁴, or —C(O)NHA; and A is lower alkyl, lower alkenyl, loweralkynyl, alkylaryl or arylalkyl, wherein one or more carbons optionallycan be replaced by N, O or S, however —Y—A—, —A—, or —AW— should notinclude two adjacent heteroatoms;

M is hydrogen, a pharmaceutically acceptable cation or a metabolicallycleavable leaving group;

X and Y are each independently O, S, S(O), S(O)₂, NR³ or CHR⁵;

Z is O, S, S(O), S(O)₂, or NR³;

R¹ and R² are each independently hydrogen, lower alkyl, C₃₋₈ cycloalkyl,halolower alkyl, halo or —COOH;

R³ and R⁴ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl,arylalkyl, C₁₋₆alkoxy-C₁₋₁₀alkyl, C₁₋₆ alkylthio-C₁₋₁₀ alkyl,heteroaryl, or heteroarylalkyl;

R⁵ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl,alkaryl, —AN(OM)C(O)N(R³)R⁴, —AN(R³)C(O)N(OM)R⁴, —AN(OM)C(O)R⁴,—AC(O)N(OM)R⁴, —AS(O)_(x)R³, —AS(O)_(x)CH₂C(O)R³, —AS(O)_(x)CH₂CH(OH)R³,or —AC(O)NHR³, wherein x is 0-2; and pharmaceutically acceptable of suchcompounds.

Compounds of Formula II have been disclosed in U.S. Pat. No. 5,703,093.As disclosed in that patent, preferred compounds of Formula II includecompounds where Ar is substituted by halo (including but not limited tofluoro), lower alkoxy (including methoxy), lower aryloxy (includingphenoxy), W (as defined above in Formula II), cyano, or R³ (as definedabove in Formula II). Those substituents are also preferred Ar groupsubstituents for compounds of other formulae disclosed herein.Specifically suitable Ar groups for the above Formula II as well as theother formulae disclosed herein include phenyl, trimethoxyphenyl,dimethoxyphenyl, fluorophenyl (specifically 4-fluorophenyl),difluorophenyl, pyridyl, dimethoxypyridyl, quinolinyl, furyl,imidazolyl, and thienyl. Additionally, in Formula II as well as otherformulae disclosed herein, W suitably is lower alkyl, such as a branchedalkyl group, e.g. —(CH2)_(n)C(alkyl)H—, wherein n is 1-5, andspecifically —(CH₂)₂C(CH₃)H—, or lower alkynyl such as of the formula—C≡C—CH(alkyl)-, including —C≡C—CH(CH₃)—.

In particularly preferred aspect, methods of the invention are employedto synthesis the following compound 1,2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran:

It has been found that biological activity, particularly 5-lipoxygenaseactivity, can vary among optically active isomers of compounds of theinvention, and therefore a single optical isomer of a compound may bepreferred. Accordingly, the synthetic methods of the invention includepreparation of enantiomerically enriched compounds of the invention.

In a first preferred aspect, substituted tetrahydrofuran compounds areprovided by reacting a hydroxy substituted aryl compound with an epoxidehaving a reactive carbon, e.g. a glycidyl compound substituted at the C3position with an electron-withdrawing group such as halo (e.g.epichlorohydrin, epibromohydrin), mesyl or tosyl (glycidyl mesylate andglycidyl tosylate), etc., to form an epoxyarylether or epoxyoaryletherin the presence of base and preferably at or above about 0° C. (As usedherein, the term “aryl” refers to both carbocyclic aryl andheteroaromatic or heteroaryl groups, which terms are further discussedbelow). That epoxyether is then reacted with an active methylenecompound to form a lactone, preferably a γ-lactone. The active methylenecompound can be a variety of agents. Diethyl and dimethyl malonate aregenerally preferred, which provide an ethyl or methyl ester as a lactonering substituent. That ester group is then removed (e.g. via hydrolysisand decarboxylation), and the lactone suitably reduced to ahydroxy-substituted tetrahydrofuran, particularly ahydroxytetrahydrofuran-aryl ether.

The hydroxy tetrahydrofuran can be further functionalized as desired,particularly by activating the hydroxyl substituent of thehydroxytetrahydrofuran-aryl ether followed by substitution of thecorresponding position of the tetrahydrofuran ring such as by a 1-alkynereagent. Also, rather than directly activating the hydroxyl moiety, thatgroup can be replaced with a halide, and the halide-substitutedtetrahydrofuran reacted with a benzylsulfonic acid reagent.

It also has been found that methods of the invention enable suchsubstitution of the tetrahydrofuran to proceed with extremely highstereoselectivity, e.g. at least greater than about 60 mole percent ofone stereoisomer than the other, more typcially greater than about 70 or75 mole percent of one stereoisomer than the other isomer.Recrystallization of such an enantiomerically enriched mixture hasprovided very high optical purities, e.g. about 95 mole %, 97 mole % oreven 99 mole % or more of the single stereoisomer.

In another aspect, methods are provided that involve cleavage of abis-compound to provide high yields of tetrahydrofuran compounds,including compounds of Formula II above. These methods preferablyinvolve condensation of mannitol with an alkanoyl compound such asformaldehyde to form a trialkylene mannitol such as a tri(C1-10alkylene)mannitol such as trimethylene mannitol where formaldehyde is employed,which is then cleaved to form 2,5,-O-methylene-mannitol, which has twoprimary hydroxyl groups and two secondary hydroxyl groups. The primaryhydroxyl groups are protected (e.g. as esters) and the secondaryhydroxyl groups then are suitably cyclized, e.g. with atrialkylorthoformate reagent, to provide a cyclic ether. The protectedprimary alcohols are then converted to aryl ethers, followed by cleavageof the cyclic ether to provide again the secondary hydroxyl groups. Themannitol compound then undergoes oxidative cleavage to provide thecorresponding alicyclic dialdehyde, which aldehyde groups arefunctionalized to bis-α,β-unsaturated esters. The carbon-carbon doublebonds of that compound are suitably saturated, and the bis-compoundcleaved and the cleavage products cyclized to provide anaryltetrahydrofuran ether which can be further functionalized asdescribed above.

In yet another aspect of the invention, preparative methods are providedthat include multiple reactions that surprisingly proceed as a singlestep without isolation of intermediates to provide oxygen ring compoundsthat have varying ring size as desired. These methods are suitable forpreparation of oxygen ring compounds having from 5 to 12 or more ringmembers, and are particularly useful for synthesis of oxygen ringcompounds having from 5 to 8 or 9 ring members.

Moreover, it has been surprisingly found that the one step procedure isenantioselective. Hence, if the starting reagent (a 2,3-epoxide) isoptically active, the resulting substituted oxygen ring compound alsowill be optically active. Moreover, the reaction proceeds withstereoselectivity, i.e. full rentention of configuration.

More particularly, in this aspect of the invention the methods includeformation, in a single step, of an alkynyl-substituted oxygen ringcompound. For preparation of an alkynyl-tetrahydrofuran, a compound isreacted that has at least a six-carbon alkyl or alklyene chain that isactivated at the 1- and 6-carbon positions such as by substitution bysuitable leaving groups, and 2- and 3-carbon positions of the chain forman epoxide ring. The leaving groups of the 1- and 6-positions may bee.g. halo, such as chloro or bromo, or an ester, such as an alkyl oraryl sulfonic ester. Preferably, the 1-position is halo-substituted,particularly bromo-, iodo- or chloro-substituted, and the 6-position issubstituted by an ester such as by a benzylsulfonyl group. That compoundis reacted with a molar excess of a strong base such as an alkyllithiumreagent that affords an alkynyl-substituted tetrahydrofuran in a singlestep.

Larger ring alkynyl-substituted compounds are readily provided throughcorresponding chain homologation of the epoxy reagent, i.e. byinterposing additional “spacing” or alkylene chain members between thereagent's activated positions.

Thus, for example, to prepare an alkynyl-substituted tetrahydopyran, areagent is employed that has at least a seven-carbon alkyl or alkylenechain that is activated at the 1- and 7-carbon positions e.g. bysubstitution by suitable leaving groups (such as those mentioned above),and the 2- and 3-positions of the chain form an epoxide ring. Thatcompound is reacted with base to provide an alkynyl-substitutedtetrahydropyran.

Similarly, to prepare an alkynyl-substituted oxepane, a reagent isemployed that has at least a seven-carbon alkyl or alkylene chainactivated (particularly by leaving groups) at the 1- and 8-carbonpositions, and the 2- and 3-postion of the chain form an epoxide ring.To prepare an alkynyl-substituted oxocane compound, a reagent isemployed that has at least eight-carbon alkyl of alkylene chainactivated at the 1- and 9-carbon positions, with the 2- and 3-positionsof the chain forming an epoxide ring. Treatment of those respectivereagents with appropriate base provides alkynyl-substituted oxepane andoxocane compounds.

In another aspect of the invention, a chiral synthon is preferablyemployed such as glyceraldehyde, mannitol, ascorbic acid, and the like,that can provide stereoselective routes to desired compounds of theinvention. This approach includes formation of a substituted dioxolane,typically a 1,3-dioxolane (particularly (2,2-dimethyl)-1,3-dioxolane),which preferably is optically active. A side chain of the dioxolane,preferably at the 4-position, is suitably extended e.g. by one or moreWittig reactions, typically one, two or more Wittig reactions thatprovide α,β-unsaturated moieties such as an α,β-unsaturated C₁₋₆alkylester. Such an α,β-unsaturated provided then can be epoxidized,preferably by asymmetric oxidation of the conjugated alkene to providean optically active epoxide, which then participates in an eliminationreaction to yield a propargyl alcohol as the dioxolane ring substituent.The dioxolane ring then can be opened, typically in the presence of acidand the acyclic intermediate cyclized to provide an optically activeoxygen alicyclic compound. See Scheme XV below and the discussionrelated thereto below. The substituted alicyclic compound can be furtherfunctionalized as desired. For instance, the primary hydroxy of thealkylhydroxy substituent of the cyclic compound can be esterified (e.g.,sulfonate such as a tosylate) and the activated methyl reacted toprovide an aryl substituent, e.g. optionally substituted phenylsubstituent. The alkynyl substituent can be extended to provided thehydroxy urea as discussed herein.

In yet a further aspect of the invention, an alkyne-substitutedtetrahydrofuran is prepared directly (e.g., without a dioxolaneintermediate) from an acyclic keto alkyne compound. More specifically, aketo alkynyl reagent with terminal alkenyl group is suitably employed,e.g. —CH₂═CH(CH₂)_(n)C(═O)C≡CR where n is an integer of 2 to 6,preferably 2 to 5, and R is suitably C₁₋₆ alkyl and the like. Theterminal alkene is then epoxidized, e.g. by ozonolysis or other suitableoxidant. The epoxidized keto alkyne then can be cyclized, e.g. in thepresence of boron methyl sulfide and the resulting oxygen alicycliccompound functionalized as desired.

Further provided are new routes to substituted hydroxy ureas. Inpreferred aspects, these routes include reaction of a protectedhydroxyurea (e.g., a compound of the formula NH₂C(O)NHOR, where R is ahydroxy protecting group such as para-methoxybenzyl-) with a substitutedalcohol in the presence of suitable dehydrating agent(s) to provide anamino ester, which is treated with ammonia and a Lewis acid to provide ahydroxy urea.

As mentioned above, compounds produced by the methods of the inventionare useful as pharmaceutical agents, particularly to treat disorders ordiseases mediated by 5-lipoxygenase such as immune, allegeric andcardiovascular disorders and diseases, e.g. general inflammation,hypertension, skeletal-muscular disorders, osteoarthritis, gout, asthma,lung edema, adult respiratory distress syndrome, pain, aggregation ofplatelets, shock, shock, rheumatoid arthritis, psoriatic arthritis,psoriasis, autoimmune uveitis, allergic encephalomyelitis, systemiclupus erythematosis, acute necrotizing hemmorrhagic encephalopathy,idiopathic thrombocytopenia, polychondritis, chronic active hepatitis,idiopathic sprue, Crohn's disease, Graves ophthalmopathy, primarybiliary cirrhosis, uveitis posterior, interstitial lung fibrosis,allergic asthma and inappropriate allergic responses to environmentalstimuli.

In other aspects, the invention provides new compounds as well aspharmaceutical compositions that comprise one or more of such compoundspreferably with a pharmaceutically acceptable carrier. Moreparticularly, the invention in a composition aspect includes compoundsof Formula I above, where n is 2 or greater (i.e. compounds withalicyclic oxygen rings that have 6 or more ring members), which includescompounds of Formulae III, IIIa, IV, IVa, V, Va, as those formulae aredefined below. The invention further provides methods for treatmentand/or prophylaxis of various disorders and diseases including thosedisclosed above such as immune, allegeric and cardiovascular disordersand diseases, the methods in general comprising administering aneffective amount of one or more compounds of Formula I above, where n is2 or greater, to a subject, such as a mammal particularly a primate suchas a human, that is suffering from or susceptible to such a disorder ordisease.

Compounds produced by the methods of the invention are useful assynthetic intermediates to prepare other compounds that will be usefulfor therapeutic applications. Other aspects of the invention aredisclosed infra.

DETAILED DESCRIPTION OF THE INVENTION

As discussed above, the invention provides methods that are particularlysuitable for synthesis of compounds of the following Formula I:

wherein Ar, Z, X, Y, R¹, n and p are as defined above.

As discussed above, in addition to the above-discussed substitutedtetrahydrofurans, methods of the invention also provide oxygen ringcompounds having 6 or more ring members.

More particularly, preferred compounds produced by the methods of theinvention include substituted tetrahydropyrans, including substitutedtetrahydropyrans of the following Formula III:

wherein Ar, Z and R¹ are each the same as defined above for Formula I,and q is an integer of from 0 to 9, and preferably q is 1, 2, 3 or 4;and pharmaceutically acceptable salts thereof.

Generally preferred are 2,6-disubstituted tetrahydropyrans, such ascompounds of the following Formula IIIa:

wherein Ar, Z, Y, W, R¹ and m are each the same as defined for FormulaII above, and q′ is an integer of from 0 to 6, and preferably q′ is 0,1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.

The methods are also particularly useful for preparations of substitutedoxepanes including compounds of the following Formula IV:

wherein Ar, Z and R¹ are each the same as defined above for Formula I,and r is an integer of from 0 to 11, and preferably r is 1, 2, 3 or 4;and pharmaceutically acceptable salts thereof.

Generally preferred are 2,7-disubstituted oxepanes, such as compounds ofthe following Formula IVa:

wherein Ar, Z, Y, W, R¹ and m are each the same as defined for FormulaII above, and r′ is an integer of from 0 to 10, and preferably r′ is 0,1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.

Still further, methods of the invention can be especially useful forsynthesis of substituted oxocanes, such as compounds of the followingFormula V:

wherein Ar, Z and R¹ are each the same as defined above for Formula I,and s is n integer of from 0 to 13, and preferably s is 1, 2, 3 or 4;and pharmaceutically acceptable salts thereof.

Generally preferred are 2,8-disubstituted oxocanes, such as compounds ofthe following Formula Va:

wherein Ar, Z, Y, W, R¹ and m are each the same as defined for FormulaII above, and s′ is an integer of from 0 to 10, and preferably s′ is 0,1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.

Preferred compounds of the invention include those having one or morehydroxy and/or alkoxy substituents on the alicyclic ring, typically one,two or three hydroxy and/or alkoxy ring substituents. Hence, in theabove formulae I, III, IIIa, IV, IVa, V, IVa, each R¹ is independentlyhydroxy or alkoxy and p is one or greater. Typical alkoxy alicyclic ringsubstituents include C₁₋₈alkoxy, more typically C₁₋₆alkoxy, still moretypically C₁₋₃alkoxy compounds. Particularly preferred compounds includethose where at least two hydroxy and/or alkoxy groups are substituentson adjacent carbons of the alicyclic ring, e.g. vicinal di-hydroxycompounds and vicinal di-alkoxy compounds.

The term alkyl, as used herein, unless otherwise specified, refers to asaturated straight, branched, or cyclic hydrocarbon and unless otherwisespecified is C₁ to C₁₀, and specifically includes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl,neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can beoptionally substituted with any appropriate group, including but notlimited to R³ or one or more moieties selected from the group consistingof halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as disclosed in Greene et al.,“Protective Groups in Organic Synthesis”, John Wiley and Sons, SecondEdition, 1991.

The term halo, as used herein, refers to chloro, fluoro, iodo, or bromo.

The term lower alkyl, as used herein, and unless otherwise specified,refers to a C₁ to C₆ saturated straight, branched, or cyclic (in thecase of C₅₋₆) hydrocarbon, and specifically includes methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl,isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl, optionally substituted asdescribed above for the alkyl groups.

The term alkenyl, as referred to herein, and unless otherwise specified,refers to a straight, branched, or cyclic (in the case of C₅₋₆)hydrocarbon of C₂ to C₁₀ with at least one double bond, optionallysubstituted as described above.

The term lower alkenyl, as referred to herein, and unless otherwisespecified, refers to an alkenyl group of C₂ to C₆, and specificallyincludes vinyl and allyl.

The term lower alkylamino refers to an amino group that has one or twolower alkyl substituents.

The term alkynyl, as referred to herein, and unless otherwise specified,refers to a C₂ to C₁₀ straight or branched hydrocarbon with at least onetriple bond, optionally substituted as described above. The term loweralkynyl, as referred to herein, and unless otherwise specified, refersto a C₂ to C₆ alkynyl group, specifically including acetylenyl,propynyl, and —C≡C—CH(alkyl)—, including —C≡C—CH(CH₃)—.

The term carbocyclic aryl, as used herein, and unless otherwisespecified, refers to non-hetero aromatic groups that have 1 to 3separate or fused rings and 6 to about 18 carbon rings members and mayinclude e.g. phenyl, naphthyl, biphenyl, phenanthracyl, and the like.The carbocyclic aryl group can be optionally substituted with anysuitable group, including but not limited to one or moieties selectedfrom the group consisting of halo, hydroxyl, amino, alkylamino,arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate,phosphonic acid, phosphate, or phosphonate, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene et al., “Protective Groups in OrganicSynthesis”, John Wiley and Sons, Second Edition, 1991, and preferablywith halo (including but not limited to fluoro), lower alkoxy (includingmethoxy), lower aryloxy (including phenoxy), W, cyano, or R³.

The term haloalkyl, haloalkenyl, or haloalkynyl refers to alkyl,alkenyl, or alkynyl group in which at least one of the hydrogens in thegroup has been replaced with a halogen atom.

The term heteroaryl, heterocycle or heteroaromatic, as used herein,refers to an aromatic moiety that includes at least one sulfur, oxygen,or nitrogen in the aromatic ring, which can optionally be substituted asdescribed above for the aryl groups. Non-limiting examples are pyrryl,furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, benzofuran,isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl,carbazolyl, benzimidazolyl, and isoxazolyl. Suitable heteroaromatic orheteroaryl groups will have 1 to 3 rings, 3 to 8 ring members in eachring and from 1 to 3 heteroatoms (N, O or S).

The term arylalkyl refers to a carbocyclic aryl group with an alkylsubstituent.

The term alkylaryl refers to an alkyl group that has a carbocyclic arylsubstituent.

The term organic or inorganic anion refers to an organic or inorganicmoiety that carries a negative charge and can be used as the negativeportion of a salt.

The term “pharmaceutically acceptable cation” refers to an organic orinorganic moiety that carries a positive charge and that can beadministered in association with a pharmaceutical agent, for example, asa counter cation in a salt. Pharmaceutically acceptable cations areknown to those of skill in the art, and include but are not limited tosodium, potassium, and quaternary amine.

The term “metabolically cleavable leaving group” refers to a moiety thatcan be cleaved in vivo from the molecule to which it is attached, andincludes but it not limited to an organic or inorganic anion, apharmaceutically acceptable cation, acryl (for example (alkyl)C(O),including acetyl, propionyl, and butyryl), alkyl, phosphate, sulfate andsulfonate.

Alkylene and heteroalkylene groups typically will have about 1 to about8 atoms in the chain, more typically 1 to about 6 atoms in the linkage.Alkenylene, heteroalkenylene, alkynylene and heteroalkynylene groupstypically will have about 2 to about 8 atoms in the chain, moretypically 2 to about 6 atoms in the linkage, and one ore moreunsaturated carbon-carbon bonds, typically one or two unsaturatedcarbon-carbon bonds. A heteroalkylene, heteroalkenylene orheteroalkynylene group will have at least one hetero atom (N, O or S) asa divalent chain member.

The term alkanoyl refers to groups that in general formulae generallywill have from 1 to about 16 carbon atoms and at least one carbonyl(C═O) moiety, more typically from 1 to about 8 carbon atoms, still moretypically 1 to about 4-6 carbon atoms. The term alkylthio generallyrefers to moieties having one or more thioether linkages and preferablyfrom 1 to about 12 carbon atoms, more preferably from 1 to about 6carbon atoms. The term alkylsulfinyl generally refers to moieties havingone or more sulfinyl (S(O)) linkages and preferably from 1 to about 12carbon atoms, more preferably from 1 to about 6 carbon atoms. The termalkylsulfonyl generally refers to moieties having one or more sulfonyl(S(O)₂) linkages and preferably from 1 to about 12 carbon atoms, morepreferably from 1 to about 6 carbon atoms. The term aminoalkyl generallyrefers to groups having one or more N atoms and from 1 to about 12carbon atoms, preferably from 1 to about 6 carbon atoms.

As discussed above, various substituent groups of the above formulae maybe optionally substituted. Suitable groups that may be present on such a“substituted” group include e.g. halogen such as fluoro, chloro, bromoand iodo; cyano; hydroxyl; nitro; azido; sulfhydryl; alkanoyl e.g. C₁₋₆alkanoyl group such as acetyl and the like; carboxamido; alkyl groupsincluding those groups having 1 to about 12 carbon atoms, preferablyfrom 1 to about 6 carbon atoms; alkenyl and alkynyl groups includinggroups having one or more unsaturated linkages and from 2 to about 12carbon atoms, preferably from 2 to about 6 carbon atoms; alkoxy groupshaving one or more oxygen linkages and from 1 to about 12 carbon atoms,preferably 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthiogroups including those moieties having one or more thioether linkagesand from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbonatoms; alkylsulfinyl groups including those moieties having one or moresulfinyl linkages and from 1 to about 12 carbon atoms, preferably from 1to about 6 carbon atoms; alkylsulfonyl groups including those moietieshaving one or more sulfonyl linkages and from 1 to about 12 carbonatoms, preferably from 1 to about 6 carbon atoms; aminoalkyl groups suchas groups having one or more N atoms and from 1 to about 12 carbonatoms, preferably from 1 to about 6 carbon atoms; carbocyclic arylhaving 6 or more carbons, particularly phenyl; aryloxy such as phenoxy;aralkyl having 1 to 3 separate or fused rings and from 6 to about 18carbon ring atoms, with benzyl being a preferred group; aralkoxy having1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms,with O-benzyl being a preferred group; or a heteroaromatic orheteroalicyclic group having 1 to 3 separate or fused rings with 3 toabout 8 members per ring and one or more N, O or S atoms, e.g.coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl,benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,morpholino and pyrrolidinyl. A “substituted” group of a compound of theinvention prepared by a method of the invention may be substituted atone or more available positions, typically 1 to about 3 positions, byone or more suitable groups such as those listed immediately above.

Particularly preferred preparative methods of the invention areexemplified in the following Schemes I through XVI. For purposes ofexemplification only, particularly preferred compounds and substituentsare depicted in the Schemes, and it will be understood that a variety ofother compounds can be employed in similar manner as described belowwith respect to the exemplified compounds. For instance, the carbocyclicaryl group of 4-fluorophenol is depicted throughout the Schemes,although a wide variety of other aryl group could be employed in thesame or similar manner as fluorophenyl. It should also be understoodthat references to “aryl” with respect to the Schemes and as otherwisespecified herein includes those groups specified for the substituent Arin Formula I above and thus encompasses carbocyclic aryl such as phenyland the like as well as heteroaryl groups. Additionally, while compoundsin the below Schemes generally depict substitution only at the ringcarbons a to the ring oxygen, other ring positions can be readilysubstituted, e.g. by using appropriately substituted starting reagents.

Scheme I exemplifies a preferred preparative method of the inventionwherein arylhydroxide 2 is reacted with epoxide 3 having a reactive C3carbon. Preferred epoxides are those that are enantiomerically enriched,such as the glycidyl tosylate 3 shown above that is condensed withphenol 2 for a time and temperature sufficient for reaction completionto provide epoxyaryl ether 4. See Example 1, Part 1 below for exemplaryreaction conditions. The reagents 2 and 3 are typically reacted in asuitable solvent, e.g. dimethyl formamide, N-methyl pyrrolidinone andthe like. Enantiomerically enriched epoxides suitable for condensationwith an arylhydroxide are commercially available or can be readilyprepared by known procedures. See, for instance, U.S. Pat. Nos.4,946,974 and 5,332,843 to Sharpless et al. for preparation of opticallyactive derivatives of glycidol.

The epoxyaryl ether 4 then is reacted with an active methylene group,such a diethyl or dimethyl malonate to provide butyrolactone 5. Theexocyclic ester of 5 is then suitably cleaved, e.g. with reaction withmagnesium chloride hexahydrate, to provide the aryllactone ether 6. SeeExample 1, Part 3 which follows for an exemplary reaction conditions.That lactone 6 is then reduced to the hydroxy-tetrahydrofuran 7.Suitable reducing agents include e.g. DIBAL-H and the like. See Example1, Part 4, which follows.

Schemes II and III exemplify further preferred methods of the inventionfor synthesis of alkynyl-substituted tetrahydrofuranaryl ethers. Morespecifically, the hydroxy substituent of tetrahydrofuran 7 is preferablyprotected, e.g. as an ether or ester. Thus, as depicted in Schemes IIand III, the hydroxy moiety of 7 can be reacted with a suitable silylreagent, e.g. to form the t-butyldimethylsilyl ether 8, or with reagentfor esterification, e.g. an anhydride such as acetic anhydride to acetylester 11. See Example 1, Part 5 and Example 2, Part 1 for suitablereaction conditions for exemplary conditions.

The protected aryltetrahydrofuran ether 8 or 11 then can reacted toprovide the alkynyl-substituted tetrahydrofuran 9 by treatment with a1-alkyne in the presence of a strong base such an alkyllithium.Preferably the alkyne reagent contains a protected hydroxy moiety suchas a silyl ether, e.g. a tetrahydropyranyl ether as depicted in theabove Schemes. The hydroxy group can be readily deprotected aftercoupling of the alkynyl reagent to the tetrahydrofuran ring, e.g. bytreatment with dilute acid. Typically, the alkyne reagent will contain aprimary or secondary hydroxy moiety.

Schemes IV and V above exemplify further convenient routes that canprovide alkynyl-substituted tetrahydrofurans of Formula I. Thus, inScheme IV, halo-substituted compound 12 can be reacted with an alkynereagent as generally described above with respect to Schemes II and IIIto provide 9, which can be readily deprotected to provide the primaryalcohol of compound 10. See generally Example 3 which follows forexemplary reaction conditions.

In Scheme V, hydroxytetrahydrofuran 7 (depicted as the lactol) iscondensed with a sulfonic acid reagent to provide the sulfonic ester 8which can be reacted with an alkyne reagent as generally described aboveto provide 9. Compound 10 is readily provided by treatment of theprotected alcohol 9 with treatment with dilute acid. See Example 4below.

Scheme VI below exemplifies a further preferred method of the inventionthat provides compounds of Formula I and involves cleavage of abis-compound to provide high yields of compounds of Formula I.

More specifically, as depicted above, trimethylene mannitol 16 issuitably prepared by condensation of mannitol 15 with formaldehyde inthe presence of acid. The labile rings are cleaved and the resultingesters of 17 reduced to the primary and secondary alcohols of 18. Theprimary alcohols are protected, e.g. as an allyl or aryl sulfonic ester,to provide intermediate 19. The secondary hydroxyl groups of 19 then arefunctionalized by reaction with a trialkylorthoformate, e.g. atri(C₁₋₁₀alkyl)orthoformate such as triethylorthoformate, to provide 20.The protected primary alcohols of 20 are then converted to aryl ethers,preferably under basic conditions by reaction with an arylhydroxidecompound such as a phenol to provide di-aryl ether 21. That aryl etheris then reacted in the presence of acid to cleave the methylene ethersto provide secondary hydroxyl groups of compound 22.

Compound 22 then undergoes oxidative cleavage by treatment with asuitable reagent such as Pb(OAc)₄, and the resulting dialdehyde isfunctionalized to the acyclic α,β-unsaturated ester 23 such as byreaction with carboethoxymethylenetriphenyl phosphorane. Otherα,β-unsaturated groups will for suitable for the alicyclic compound,e.g. α,β-unsaturated esters have 1 to about 12 carbon atoms,α,β-unsaturated acids, and other Michael-type acceptors. Thecarbon-carbon double bonds of 23 then are saturated, preferably byhydrogenation, and the resulting compound is cleaved and cyclized in thepresence of acid to form the aryl ether 6. In one system, the saturatedcompound is refluxed in a suitable solvent such as an alcohol, ethanol,for a time sufficient to provide 6. See Example 5 which follows forexemplary reagents and reaction conditions. Compound 6 then can befurther functionalized, e.g. as discussed above with respect to SchemesII and III.

Scheme VII above exemplifies a further preferred method of the inventionthat provides compounds of Formula I and features multiple reactionsthat proceed as a single step without isolation of intermediates.

More specifically, as shown above aryl compound 2 is reacted withepoxide 24 that has a reactive C3 carbon to provide the arylepoxy ether25. If the epoxide 24 is not enantiomerically enriched such as 3, thearylepoxy ether 25 may be resolved if desired such as by proceduresgenerally depicted in Scheme VI above to provide optically activeepoxide ethers 27 and 4. See Example 6, Parts 2-4 below for exemplaryreagents and reaction conditions. That procedure generally entailsformation of optically active aryldiol ether and arylepoxide ether 26and 27 from the racemic arylepoxide 25 with an optically active reagent,preferably an optically active catalyst such as Jacobsen's catalyst. SeeE. Jacobsen, Science, 277:936-938 (1997). The optically active diol 26can be readily cyclized to the epoxide 4, for example by esterification(e.g. a sulfonic ester as shown exemplified by 28 above) of the primaryhydroxyl group of the diol followed by epoxide formation under basicconditions (e.g. NaH).

An allyl halide is suitably reacted with the arylepoxide ether, suitablyin the presence of Mg, catalytic amount of iodine and cuprous cyanide toprovide aryl/alkene ether 29. The secondary hydroxy is suitablyprotected, e.g. as an ester, preferably as a sulfonic ester, to provide30. An ester group is then suitably grafted to terminal carbon-carbondouble bond to the α,β-unsaturated ester 31, and the ester reduced tothe alcohol, typically by treatment with strong base such as DIBAL-H.

The alkene is then suitably oxidized to provide epoxy group of 33. Theoxidation may be conducted to provide optically active epoxy carbons asgenerally shown in Scheme VI (compound 33) and conducted using suitableoptically active reagent(s) such as an optically catalyst or otherreagent. See Example 6, Part 9 for an exemplary procedure. The racemicepoxides also may be resolved, e.g. by chromatography using an opticallyactive packing material. The glycidyl compound 33 is then converted tothe epihalohydrin 34.

The epihalohydrin 34, in a single step, is converted to thealkynyltetrahydrofuran ether 35 upon treatment with a molar excess,preferably at least about a three molar excess of a strong base such asan alkyllithium reagent or sodium amide. BuLi is generally preferred,particularly n-BuLi.

While not being bound by theory, it is believed the single step reactionproceeds through the mechanism shown immediately below, where Ar is thesame as defined for Formula I and Ms is mesyl (—S(O)₂CH₃):

The alkynyl group of compound 35 can be further functionalized asdesired, e.g. by reaction with ethylene oxide in the presence of base toafford the single enantiomer 10.

Compound 10 also can be further functionalized as desired. For example,to produce compound 1 as shown above, compound 10 can be reacted withN,O-bisphenoxycarbonyl hydroxylamine and triphenylphosphine anddiisopropylazodicarboxylate, followed by treatment of resultingintermediate with NH₃.

However, in a preferred aspect and as discussed above, the inventionprovides new routes to substituted hydroxy ureas. More particularly, aprotected hydroxyurea (e.g., a compound of the formula NH₂C(O)NHOR,where R is a hydroxy protecting group such as an alkyl, aryl orpreferably aryalkyl ether such as an ether of an optionally substituted(phenyl)OCH₂—) is reacted with a substituted alcohol compound such as 10of Scheme II, preferably in the presence of suitable dehydratingagent(s) such as triphenyl phosphine and diethylazodicarboxylate (DEAD)to provide an amino ester, i.e. a moiety of the formula —NRC(O)OR¹Rwhere R is as defined immediately above and R¹ is a non-hydrogen groupsuch as aryl, particularly phenyl, alkyl, e.g. C₁₋₁₀ alkyl, etc. Thatamino ester is then treated with ammonia and a Lewis acid such as borontrifluoride etherate and the like to provide a hydroxy urea.

Schemes VIII, IX and X exemplify preferred methods for synthesis ofsubstituted oxepanes in accordance with the invention.

Thus, as generally shown in Scheme VIII above, the halo benzyloxyalkane41 is condensed with an arylether oxirane in the presence of anappropriate metal for a time and temperature sufficient for reactioncompletion to provide the arylbenzylether hydroalkane 42. The hydroxylfunctionality of the arylether 42 is suitably protected especially as anether such as methoxyethoxymethyl ether, methoxymethyl ether ortetrahydropyranyl ether and the like to provide the intermediate 43. Thebenzyl protection group of arylether 43 is removed under appropriateconditions such as hydrogenation using palladium on activated carbon.The resulting primary alcohol 44 is then oxidized to the correspondingaldehyde 45 using an appropriate oxidizing agent such as oxalyl chlorinewith dimethyl sulfoxide in an appropriate solvent such as methylenechloride or chloroform, or a buffered solution of pyridinium dichromatein dry methylene chloride.

The hydroxy group of 49 can be readily deprotected after coupling of thealkynyl reagent to the oxepane ring, e.g. by treatment with dilute acidsuch as a 1% HCl methanol solution to provide the alkynylhydroxysubstituted oxepane 50 as shown in Scheme X. The aryletheralkynylhydroxy oxepane 50 can be further functionalized as desired e.g.by amidation using a N,O-substituted hydroxylamine, preferably in thepresence of dehydrating reagents such as triphenylphosphine anddiisopropylazodicarboylate, followed by treatment of the resultingintermediate 51 with ammonia to yield the hydroxylamine oxepane 52. Seethe above discussion and Example 7, Parts 9 and 10 which follow forexemplary reaction conditions.

Synthetic methods of the invention also include preparation of compoundsuseful as intermediates to prepare 2,7-disubstituted tetrahydropyrancompounds of the above Formula 1.

Schemes XI, XII and XIII exemplify some preferred preparative methods ofthe invention for synthesis of alkynyl-substituted tetrahydropyrans.

Generally as shown is Scheme XI, the epoxy aryl ether 4, is reacted witha 1-alkyne reagent in the presence of a strong base such as butyllithium and boron trifluoroetherate in THF to yield the alkyne 56.Preferably the alkyne reactant contains an ester moiety such as a methylester. The alkynyl functionality of arylether 56 is reduced underappropriate conditions such as hydrogenation using palladium onactivated carbon as catalyst in an appropriate solvent such as methanolor ethanol to yield the alkane 57. Rearrangement with cyclization of thearylether methyl ester 57 is done by treatment with toluenesulfonic acidpreferably in an appropriate solvent such as toluene to yield thetetrahydropyrrolinone 58.

The aldehyde 58 is reduced, e.g. by reaction with dilsobutylaluminumhydride to yield the corresponding alcohol 58 as shown in Scheme XII.The arylether alcohol 59 and benzylsulfonic acid react in an appropriatesolvent such as methylene chloride or chloroform in the presence of adrying agent such as calcium chloride to afford the cyclized aryletherbenzylsulfinic tetrahydropyran 60. The benzylsulfinic tetrahydropyran 60can then react with a 1-alkyne in the presence of magnesium andisopropyl bromide to provide the alkynyl-substituted tetrahydropyran 61.Preferably the alkyne reactant contains a protected hydroxyl moiety suchas tetrahydropyranyl ether or t-butyldimethylsilyl ether. It has beensurprisingly found that reaction of the alkyne reagent with a mixture ofa stereoisomers of 60 (i.e. racemic at phenylsulfinic-substituted ringcarbon) proceeds stereoselectively to produce the trans compound 61. Infact, it has been found that the trans 61 compound can be the exclusivereaction product. The hydroxy group of 61 can be readily deprotectedafter coupling of the alkynyl reagent to the oxepane ring, e.g. bytreatment with dilute acid such as a 1% HCl methanol solution to providethe alkynylhydroxy substituted tetrahydropyran 62.

The arylether alkynylhydroxy tetrahydropyran 62 can be purified to yieldthe enantiomerically enriched disubstituted tetrahydropyran 63. Thearylether alkynylhydroxy tetrahydropyran 63 further functionalized asdesired by amidation using a N,O-substituted hydroxylamine, preferablyin the presence of dehydrating reagents such as, triphenylphosphine anddiisopropylazodicarboylate, followed by treatment of the resultingintermediate 64 with ammonia to yield the hydroxylamine tetrahydropyran65.

Synthetic methods of the invention also include preparation of compoundsuseful as intermediates to prepare 2,7-disubstituted oxepane compoundsof the above Formula II.

Scheme XIV below another preferred preparative method of the inventionthat employs a polyol (polyhydroxy) reagent. As depicted in the belowScheme, the entire reaction is stereoselective (i.e. no separateresolution step or procedure required), beginning with the opticallyactive glyceraldehyde 1, which is commercially available. Otherglyceraldehyde stereoisomers can be employed in the same manner asdepicted in Scheme VIII to provide the corresponding distinctstereoisomer as the reaction scheme product.

In the following Schemes XIV through XVI, the compound numerals in thediscussions of those Schemes are made in reference to the compounddepicted in the particular Scheme, with the exception of compound 1,i.e.2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran.

As generally exemplified in Scheme XIV below, the chiral synthon(glyceraldehyde) is cyclized in the presence of base to thebis-dioxolane compound 2 which is then oxidized to the keto (aldehyde)dioxolane 3 and reacted with an appropriate Wittig reagent to providethe α,β-unsaturated ester 4. As referred to herein, unless specifiedotherwise, the term “Wittig reaction” or “Wittig-type reaction”designates any of the broad classes of alkene-formation reactions,typically involving ylide intermediates such as may be provided byphosphonate and phosphorane reagents. Additionally, as referred toherein, unless otherwise specified, to “keto”, “carbonyl”, or “carboxy”or like term designate any functional group that includes acarbon-oxygen double bond (C═O).

The carbon-carbon double bond produced by the Wittig reaction then canbe saturated, e.g. hydrogenated in the presence of a suitable catalystsuch as PtO₂, and the ester reduced and then oxidized to providealdehyde 7. Wittig reaction of the aldehyde moiety provides theα,β-unsaturated compound 9 which can be reduced to alcohol 9, andconverted to the propargyl compound, e.g. via an epoxidizedintermediate. More specifically, unsaturated alcohol 9 can be epoxidizedto compound 10, suitably with an optically active oxidant and thenelimination of the epihalohydrin derivative 11 in the presence of asuitable base e.g. LDA or other suitable agent to provide the propargylcompound 12. Additional, successive Wittig-type reactions withintervening carbon-carbon double bond saturation and aldehyde formationcan be employed to prepare larger oxygen ring compounds. Thus, toprepare six-member oxygen alicyclic compounds of the invention, thesequence of steps shown in Scheme XIV below in the transformation ofcompound 3 to 7 would be repeated to compound 9a (which is compound 9oxidized to the corresponding aldehyde). Similarly, to prepare sevenmember oxygen alicyclic compounds of the invention, the sequence ofsteps shown in Scheme XIV below in the transformation of compound 3 to 7would be repeated two more times; to prepare eight member oxygenalicyclic compounds of the invention, the sequence of steps shown inScheme XIV below in the transformation of compound 3 to 7 would berepeated three more times beyond that shown in the Scheme.Alternatively, or in combination with successive Wittig reactions, otherWittig reagents can be employed that provide for greater chain extensionin a single step, e.g. Ph₃P═CHCH₂CO₂Et, Ph₃P═CHCH₂CH₂CO2Et, and thelike, or corresponding Wadsworth-Emmons reagents.

Acidic opening of the dioxolane ring provides diol 14 and esterification(e.g. sulfonate ester such as a tosylate) provides the substitutedtetrahydrofuran 16. The resulting hydroxy tetrahydrofuran can befunctionalized as desired, e.g. esterification of the hydroxy followedby aryl substitution and functionalization of the alkynyl group providescompound 1, particularly2S,5S-trans-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran.See, generally, Example 11 which follows for exemplary preferredreaction procedures.

Scheme XV depicts a related approach to provide another stereoisomer ofa substituted oxygen alicyclic compound. As shown in Scheme XV,L-ascorbic acid can be employed as a starting reagent to provide hydroxydioxolane compound 19, which is oxidized; subjected to multiple Wittingreactions; epoxidized; and an epihalohydrin intermediate reacted in thepresence of base to form a proparoyl alcohol intermediate, which isconverted to the optically active aryl-substituted alkynetetrahydrofuran compounds 33 and 34. To produce larger ring compounds,additional, successive Wittig reactions can be carried out, as discussedabove with respect to Scheme XIV.

It should be appreciated that the unsubstituted alkyne produced throughthe routes of Schemes XIV and XV above is a versatile intermediate thatcan be further reacted to provide a wide range of moieties, includinggroups that can be detected, either upon in vitro or in vivoapplications. For instance, the unsubstituted alkyne can be reacted witha group to provide radiolabeled and stable isotopic moieties, e.g. ¹²⁵I,³H, ³²P, ⁹⁹Tc, ¹⁴C, ¹³C, ¹⁵N or the like, which may be useful inter aliafor mechanistic studies.

Scheme XVI below depicts highly efficient routes to oxygen alicycliccompounds of the invention. As shown in the Scheme, butynyl reagent 52is treated with base, preferably a strong base such as an alkyl lithiume.g. butyl lithium, and then reacted with an unsaturated anhydride 53 toprovide the keto alkynyl compound 54 with terminal alkene group. Thealkene group is oxidized, e.g. via ozonolysis, and the keto-epoxidecompound 55 reduced and cyclized in the presence of a suitable reducingagent, e.g. borane dimethyl sulfide. The resulting hydroxytetrahydrofuran can be functionalized as desired, e.g. esterification ofthe hydroxy moiety followed by aryl substitution and functionalizationof the alkynyl group provides2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran.See Example 12 which follows for exemplary preferred reactionconditions.

Larger ring compounds also can be prepared by this general route, e.g.by reaction of corresponding ring-extended compounds corresponding tocompound 53 below. That is, to prepare oxygen alicyclic compounds havingsix ring members, the compound CH₂═CH(CH₂)₃C(═O)OCOOEt can be employedin place of compound 53 in the below Scheme; to prepare oxygen alicycliccompounds having seven ring members, the compoundCH₂═CH(CH₂)₄C(═O)OCOOEt can be employed in place of compound 53 in thebelow Scheme; and to prepare oxygen alicyclic compounds having eightring members, the compound CH₂═CH(CH₂)₄C(═O)OCOOEt can be employed inplace of compound 53 in the below Scheme.

Schemes XVII and XVIII below depict routes to alicyclic compounds of theinvention having one or preferably more hydroxy or alkoxy (e.g. C₁₋₁₂alkoxy, more preferably C₁₋₈ or C₁₋₆ alkoxy) substituents, preferablytwo hydroxy or alkoxy substituents on adjacent (vicinal) ring positionsof the alicyclic compound. Thus, as shown in Scheme XVII below, mannosediacetonide 70 is converted to sulfide 72 followed by hydrolysis toprovide 73. The alkylhydroxy ring substituent of 73 can befunctionalized as desired, e.g. activation of a carbon such as byesterification (e.g. sulfonate, such as tosylate, mesylate, etc.) andnucleophilic substitution of the activated carbon, e.g. by an arylnucleophile, particularly a carbocyclic aryl nucleophile such as aoptionally substituted phenol. Other ring positions can befunctionalized as desired, e.g. as shown in Scheme XVII, the sulfidegroup can be oxidized to the sulfone 74 to activate the ring carbon andthat position substituted by a suitable reagent, e.g. a terminal alkyne,to provide compound 75. The vicinal alkoxy groups of compounds 75 and 76can be readily converted to the corresponding vicinal di-hydroxy groupsby acidic hydrolysis. Scheme XVIII shows alternate functionalization ofthe alicyclic compound. The di-alkoxy compounds 85 and 86 can beconverted to the corresponding vicinal di-hydroxy compounds by acidichydrolysis.

Often, it will be preferable to use an optically active orenantiomerically enriched mixture of a chiral compound of the inventionfor a given therapeutic application. As used herein, the term“enantiomerically enriched” refers to a compound mixture that is atleast approximately 85% or 90%, and preferably a mixture ofapproximately at least about 95%, 97%, 98%, 99%, or 100% of a singleenantiomer of the compound.

As discussed above, compounds of the invention are useful for numeroustherapeutic applications. The compounds can be administered to asubject, particularly a mammal such as a human, in need of treatment, bya variety of routes. For example, the compound can be administeredorally, parenterally, intravenously, intradermally, subcutaneously, ortopically. For example, for parenteral application, particularlysuitable are solutions, preferably oily or aqueous solutions as well assuspensions, emulsions, or implants, including suppositories. Ampulesare convenient unit dosages. For enteral application, particularlysuitable are tablets, degrees or capsules e.g. having talc and/orcarbohydrate carrier binder or the like, the carrier suitably beinglactose and/or corn starch and/or potato starch.

The active compound may be administered to a subject as apharmaceutically active salt, e.g. salts formed by addition of aninorganic acid such as hydrochloric acid, hydrobromic acid, phosphoricacid, etc., or an organic acid such as acetic acid, oxalic acid,tartaric acid, succinic acid, etc. Base addition salts also can beformulated if an appropriate acidic group is present on the compound.For example, suitable base addition salts include those formed byaddition of metal cations such as zinc, calcium, etc., or salts formedby addition of ammonium, tetraethylammonium, etc. Suitable dosages for agiven therapy can be readily determined by the medical practitionerbased on standard dosing protocols. See also U.S. Pat. No. 5,703,093.

All documents mentioned herein are incorporated herein by reference. Thefollowing non-limiting examples are illustrative of the invention.

EXAMPLE 1 Preparation of(2S)(5R)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran(Scheme II; 10) Part 1: (S)-Glycidyl-4-fluorophenyl ether (Scheme I; 4)

In a 100 ml two-necked round bottom flask equipped with magnetic stirbar, nitrogen inlet and a septum, was taken sodium hydride (60%dispersion in oil, 0.742 g, 0.0185 mol) and 10 mL of dry dimethylformamide (DMF). The reaction mixture was cooled to 0° C. and4-fluorophenol 2 (1.9 g, 0.017 mol) in dry DMF (20 mL) was introduced.The reaction mixture was stirred at room temperature for 1 hour andcooled to 0° C. (S)-Glycidyl tosylate 3 (3.52 g, 0.015 mol) in DMF (10mL) was added, and the reaction mixture was stirred at room temperatureand monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.5). After 4hours, the reaction mixture was quenched by addition of ice-water (1 mL)and extracted with (2×25 mL) ethyl ether. The ether layer was washedwith water, brine, dried over Na₂SO₄ and concentrated under reducedpressure to afford (S)-glycidyl-4-fluorophenyl ether 4, crude yield 3.6g. The crude compound was purified by distillation at 160°-170° C./9 mm,to yield 1.98 g (76%) of purified product 4, [α]_(D)+4.96° (c 2.335,CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ 2.68 (dd, J=4.5, 2.2 Hz, 1 H), 2.85(t, J=4.5 Hz, 1 H), 3.27 (m, 1 H), 3.89 (dd, J=15.7, 6.7 Hz, 1 H), 4.11(dd, J=15.7, 4.5 Hz, 1 H), 6.74-7.02 (m, 4 H).

Part 2: (4S)-2-carboethoxy-(4-fluoro-phenoxy-methyl)-γ-butyrolactone(Scheme I; 5)

In a 50 ml two-necked round bottom flask equipped with magnetic stirbar, nitrogen inlet septum, sodium salt of diethyl malonate (preparedfrom 1.8 mL/0.0118 mol of diethyl malonate and 0.245 g/0.0106 mol ofsodium) in dry THF (10 mL) was taken. The reaction mixture was cooled to0° C. and (S)-glycidyl-4-fluorophenyl ether 4 (1.788 g, 0.0106 mol) intetrahydrofuran (THF) (10 mL) was added. The reaction mixture wasstirred at room temperature and monitored by TLC, (EtOAc-light petroleum1:3, Rf=0.30). After 12 hours, THF was removed on rotavapor. The residuewas dissolved in ethyl acetate (25 mL) and washed with water, brine,dried over Na₂SO₄ and concentrated on rotavapor to afford(4S)-2-carboethoxy-(4-fluoro-phenoxy-methyl)-γ-butyrolactone 5, with acrude yield of 2.816 g. That crude product was purified on silica gelcolumn chromatography using EtOAc-light petroleum ether (1:8) to provide2.10 g (70%) of purified product 5, m.p.69-71° C., [α]_(D)+16.95° (c1.51, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ 1.3 (m, 3 H), 2.37-2.9 (m, 2H), 3.52-3.8 (m, 1 H), 3.95 4.32 (m, 4 H), 4.68-4.82 (m, 1/3 H),4.82-4.98 (m, 2/3 H), 6.72-7.01 (m, 4 H). It is also noted that thecrude product can be suitably employed directly in the decarboxylativeelimination of Part 3 below.

Part 3: (4S)-4-fluorophenoxy-methyl)-γ-butyrolactone (Scheme I; 6)

(4S)-2-carboethoxy-(4-fluoro-phenoxy-methyl)-γ-butyrolactone 5 (2.1 g,0.0074 mol) and N,N-dimethylacetamide (10 mL) were taken in a 25 mLround bottom flask equipped with a stir bar and reflux condenser. MgCl₂6H₂O (1.51 g, 0.0074 mol) was added, and the reaction mixture was heatedunder reflux for 4 hours and monitored by TLC (EtOAc-light petroleum1:2, Rf=0.2). The reaction mixture then was partitioned between ethylether and water (50 mL each). The ether layer was separated, washedtwice with water, brine, dried over Na₂SO₄ and concentrated on rotavaporto afford (4S)-4-fluorophenoxy-methyl)-γ-butyrolactone 6, yield 1.40 g(90%), m.p. 58-59° C., [α]_(D)+23° (c 1.99, CHCl₃), e.e. 92%. ¹H NMR(200 MHz, CDCl₃): δ 2.13-2.80 (m, 4 H), 4.02 (dd, 1 H, J=4.5, 9.0 Hz),4.11 (dd, 1 H, J=4.5, 9.0 Hz), 4.80 (m, 1 H), 6.75=7.02 (m, 4 H).

Part 4: (2S)-(4-Fluorophenoxymethyl)-5-hydroxytetrahydrofuran (Scheme I;7)

A flame dried 100 mL two neck round bottom flask equipped with amagnetic stir bar and nitrogen inlet was charged with a solution of 3.5g (0.0167 mol) of (4S)-4-fluorophenoxy-methyl)-γ-butyrolactone 6 in 30mL of CH₂Cl₂. That solution was cooled to −78° C. and 7.34 mL (0.018mol) diisobutylaluminum hydride (DIBAL-H; 2.5M solution in hexane) wasadded dropwise. The reaction mixture was stirred at −78° C. for 3 hours.The reaction mixture was quenched with methanol (5 mL) and saturatedaqueous solution of potassium sodium tartrate. The organic layer wasseparated, dried over Na₂SO₄ and concentrated on rotavapor to provide(2S)-(4-fluorophenoxymethyl)-5-hydroxytetrahydrofuran 7 as a solid (3.47g). This crude lactol was used in the next reaction (Part 5) withoutfurther purification.

Part 5: (2S)(4-fluoophenoxymethyl)-5-(tert-butyldimethylsiloxy)-tetrahydrofuran)(Scheme II; 8)

A solution of 3.47 g of(2S)-(4-fluorophenoxymethyl)-5-hydroxytetrahydrofuran 7 in 30 mL ofCH₂Cl₂ was taken in an 100 mL round bottom flask equipped with amagnetic stir bar and nitrogen inlet. That solution was cooled in anice-water bath and 2.18 g (0.032 mol) of imidazole was added, followedby a solution of 3.6 g (0.024 mol) of tert-butyldimethylsilylchloride(TBDMSCl) in 30 mL of CH₂Cl₂. The reaction mixture then was stirred atroom temperature for 3 hours, and the reaction then quenched with icewater, the organic layer separated, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography using light petroleum ether: ethyl acetate (9:1) to yield(2S)(4-fluoophenoxymethyl)-5-(tert-butyldimethylsiloxy)-tetrahydrofuran) 8as an oil (5.1 g, 95%). ¹H NMR (200 MHz, CDCl₃): δ 0.09 (s, 6 H), 0.88(s, 9 H), 1.72-2.34 (m, 4 H), 3.76=4.08 (m, 2 H), 4.28-4.54 (m, 1 H),5.47 (s, 1/3 H), 5.54 (d, J=4.5 Hz, 2/3 H), 6.75-7.0 (m, 4H).

Part 6: (2S) (5SR)(4-fluoophenoxymethyl)-5-(1-butynyl-4-tert-butyldimethylsiloxy)-tetrahydrofuran(Scheme II; 9)

To a flame dried 100 mL two neck round bottom flack equipped with amagnetic stir bar and nitrogen inlet and septum was added a solution of5 g (0.0154 mol) of (2S)(4-fluoophenoxymethyl)-5-(tert-butyldimethylsiloxy)-tetrahydrofuran) 8in 25 mL of CH₂Cl₂. That solution was cooled to −78° C. and 2.82 mL(0.0184 mol) of trimethylsilylbromide (TMSBr) was added dropwise. Thereaction mixture was then stirred at −78° C. for 3 hours.

In a separate flame dried 50 mL two neck round bottom flask equippedwith a magnetic stir bar, nitrogen inlet and septum was added a solutionof 3.4 g (0.0184 mol) of 4-tert-butyl-dimethylsiloxy-1-butyne in 30 mLof THF. That solution was cooled to −78° C. and 15.4 mL (1.5M solutionin hexane; 0.023 mol) of n-BuLi was added dropwise. That reactionmixture was stirred at −78° C. for 1 hour, and then transferred viasyringe to the TMSBr solution. The combined solutions were stirred at−78° C. for 2 hours, and then the reaction quenched with saturatedammonium chloride solution (20 mL) and the organic layer separated. Theaqueous layer was extracted with CH₂Cl₂ and the combined organic layerswere dried over Na₂SO₄ and then concentrated under reduced pressure toafford (2S) (5SR)(4-fluoophenoxymethyl)-5-(1-butynyl-4-tert-butyldimethylsiloxy)-tetrahydrofuran9 as a thick syrup (6.0 g; 97%).

Part 7: (2S)(5RS)-2-(4-Fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran(Scheme II; 10)

Without further purification, (2S) (5SR)(4-fluoophenoxymethyl)-5-(1-butynyl-4-tert-butyldimethylsiloxy)-tetrahydrofuran9 as prepared in Part 6 above was dissolved in 25 mL of methanol in a 50mL single neck round bottom flask. That methanol solution was cooled inan ice-water bath and 3 mL of 1% HCl solution in methanol was added. Thereaction mixture was then stirred at room temperature for 3 hours,followed by neutralization with saturated aqueous sodium bicarbonatesolution. After removal of methanol under reduced pressure, theresulting residue was dissolved in 100 mL of ethyl acetate. The organiclayer was washed with water and brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography using light petroleum ether: ethyl acetate (1:1) toprovide (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran 10 as athick syrup (4.0 g, 96%). ¹H NMR (200 MHz, CDCl₃): δ 1.76-2.32 (m, 4 H),2.46 (dt, 2 H, J-2.2, 6.7 Hz), 3.69 (t, 2 H, J=6.7 Hz), 3.89 (d, 2 H,J=4.5 Hz), 4.41 (m, 1 H), 4.70 (m, 1 H), 6.73-6.98 (m, 4 H).

EXAMPLE 2 Alternate Preparation of (2S)(5RS)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran(Scheme III; 10) Part 1: (2S)(5RS)-5-O-acetyl-2-(4-fluoro-phenoxymethyl)tetrahydrofuran (Scheme III;11).

To a 25 ml round bottom flask with magnetic stir bar, (2S)(5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy tetrahydrofuran 7 (1.0 g,0.0047 mol) in CH₂Cl₂ (5 mL) was added. The solution was cooled in anice-bath, pyridine (0.8 mL), acetic anhydride (0.9 mL) and DMAP(catalytic amount) were added in succession. The reaction was monitoredby TLC (EtOAc-light petroleum ether 1:3, Rf=0.5). The reaction mixturewas diluted with CH₂Cl₂ (10 mL) washed with 5% HCl, brine and dried overNa₂SO₄. The solvent was removed on rotavapor to give (2S)(5RS)-5-O-acetyl-2-(4-fluoro-phenoxymethyl)tetrahydrofuran 11 (1.05 g,88%). ¹H NMR (200 MHz, CDCl₃): δ 1.98, 2.05 (2s, 3 H), 1.89-2.3 (m, 4H), 3.85-4.09 (m, 2 H), 4.36-4.61 (m, 1 H), 6.26 (s, ½ H), 6.33 (d,J=4.5 Hz, ½ H), 6.75-7.01 (m, 4 H).

Part 2: (2S) (5SR)(4-fluorophenoxymethyl)-5-(1-butynyl-4-tert-butyldimethylsiloxy)-tetrahydrofuran(Scheme III; 9).

To a flame dried 25 ml two-necked round bottom flask equipped withmagnetic stir bar, nitrogen inlet and a septum, was added a solution of(2S) (5RS)-2-(4-fluorophenoxy-methyl)-5-O-acetyl tetrahydrofuran 11(1.05 g, 0.004 mol) in CH₂Cl₂ (12 mL). The solution was cooled to 78° C.and TMS-Br (0.65 ml, 0.0049 mol) was added dropwise. The reactionmixture was stirred at −78° C. for 3 hours (monitored by TLC,EtOAc-light petroleum 1:4, Rf=0.4). In a separate flame dried 50 mLtwo-necked round bottom flask equipped with magnetic stir bar, nitrogeninlet and a septum, a solution of 4-tert-butyldimethylsiloxy-1-butyne(0.913 g, 0.0049 mol) in THF (15 mL) was taken. The solution was cooledto −78° C. and n-BuLi in hexane (1.5M, 4.13 mL, 0.0062 mol) was addeddropwise. The reaction mixture was stirred at −78° C. for 1 hour. Thissolution was transferred via cannula to the reaction mixture of step 3at −78° C. The reaction was monitored by TLC (EtOAc-light petroleum 1:4,Rf=0.7) and completed in 2 hours. The reaction mixture was quenched withsaturated ammonium chloride solution (10 mL). THF was removed underreduced pressure and extracted with CH₂Cl₂ (2×10 mL) dried over Na₂SO₄and concentrated, to provide a crude yield of 1.7 g of (2S) (5SR)(4-fluoophenoxymethyl)-5-(1-butynyl-4-tert-butyldimethylsiloxy)-tetrahydrofuran9.

Part 3: (2S)(5RS)-2-(4-Fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran(Scheme III; 10)

The crude product 9 (1.7 g) as prepared in Part 2 above was dissolved inmethanol (10 mL), and 1% HCl solution in methanol (5 mL) was added.After 3 h the reaction mixture was neutralized with saturated aqueoussodium bicarbonate. After removal of methanol on rotavapor, the residuewas dissolved in ethyl acetate (15 mL). The EtOAc fraction was washedwith water, brine, dried over Na₂SO₄ and concentrated on rotavapor. Theresidue afforded (2S)(5Rs)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran10 as a thick syrup (0.957 g, 88%).

EXAMPLE 3 Further Alternate Preparation of (2S)(5RS)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran(Scheme IV; 10) Part 1: (2S)(5RS)-5-bromo-2-(4-fluorophenoxymethyl)tetrahydrofuran (Scheme IV; 12)

(2S) (5RS)-5-bromo-2-(4-fluorophenoxymethyl)tetrahydrofuran was preparedfrom (2S) (5RS)-5-O-acetyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 11(1.06 g, 0.00417 mol) and TMS-Br (0.65 mL, 0.0049 mol).

Part 2: (2S)(5RS)-2-(4-fluorophenoxymethyl)-5-(4-tetrahydropyranoyloxybutyn-1-yl)-tetrahydrofuran(Scheme IV; 13)

In a flame dried 50 mL two-necked RB flask equipped with a magnetic stirbar, nitrogen inlet and a septum 4-tetrahydropyranoyl-1-butyne (0.774 g,0.005 mol) in THF (10 mL) was taken and cooled to −78° C. A solution ofn-BuLi in hexane (1.5 M, 4.2 mL, 0.0063 mol) was added dropwise, and thereaction mixture was stirred at −78° C. for 1 hour. This solution wastransferred via cannula to the reaction mixture of art 1 of this exampleat −78° C. That reaction mixture was stirred at −78° C. for 2h andmonitored by TLC (EtOAc-light petroleum 1:4, Rf=0.7). The reactionmixture was quenched with saturated ammonium chloride solution and THFwas removed on rotavapor. The residue was partitioned between CH₂Cl₂ (20mL) and water, and the organic layer was separated, washed with water,brine dried over Na₂SO₄ and concentrated on rotavapor to provide a crudeyield of 1.73 g.

Part 3: (2S)(5RS)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran(Scheme IV; 10)

That crude product 13 (1.73 g) was dissolved in MeOH (10 mL) and 1% HClin methanol (5 mL) was added. After 2.5 h, the reaction mixture wasquenched by saturated aqueous NaHCO₃, and concentrated under reducedpressure. The residue was dissolved in EtOAc (20 mL), washed with water,brine, dried over Na₂SO₄ and concentrated to give (2S)(5RS)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran10 (1.03 g, 93%). HPLC analysis: Column ODS; flowrate: 1.0 mL/min.; UV:225 nm. Mobile phase 60% methanol in water. Trans:cis ratio (65:35).

EXAMPLE 4 Further Alternate Preparation of(2S)(5RS)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran(Scheme V: 10) Part 1: (2S)(5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran (SchemeV; 14)

To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25% HCl wasadded dropwise with stirring until the solid dissolved. The reactionmixture was extracted (100 mL each, 3 times) with EtOAc, dried overNa₂SO₄ and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61g, 0.0324 mol), CaCl₂(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL)were added. The reaction mixture was cooled to 0° C. and (2S)(5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216mol) in dry CH₂Cl₂ (20 mL) was added. The reaction mixture was stirredfor 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25).The reaction mixture was filtered through celite and washed with CH₂Cl₂(3 times). The combined organic layer was washed with saturated aqueousNa₂CO₃, water brine and dried over Na₂SO₄. Solvent was removed underreduced pressure to afford the crude (2S)(5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14which was crystallized from chloroform-hexane to give pure white solid,yield 6.8 g (93%), m.p. 102° C.-104° C. ¹H NMR (200 MHz, CDCl₃): δ1.90-3.0 (m, 4 H), 3.85-5.0 (m, 4 H), 6.70-7.05 (m, 4 H), 7.45-7.72 (m,3 H), 7.77-8.0 (m, 2 H).

Part 2: (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-(4-tetrahydropyranoyl-1-butyne)-tetrahydrofuran(Scheme V; 9)

To a 250 ml two-necked RB flask equipped with magnetic stir bar,nitrogen inlet and a septum, Grignard grade magnesium (2.0 g, 0.0833mol) was taken and the flask flame dried along with magnesium. The flaskwas cooled to room temperature and dry THF (5 mL) was added followed by1,2-dibromoethane (catalytic amount) to activate the magnesium.Isopropylbromide (8.78 g, 0.0714 mol) in THF (140 mL) as added dropwiseover 15 min. The reaction mixture was stirred for 1 hour. The isopropylmagnesium bromide was cannulated in a 1000 mL flame dried two-neckedround bottom flask with spin-bar, nitrogen inlet and septum.4-Tetrahydropyranoyl-1-butyne (11.0 g, 0.0714 mol) in THF (140 mL) wasadded. The reaction mixture was stirred for 30 min. and cooled at 0° C.Freshly prepared ZnBr₂ solution (1M, 43 mL, 0.0428 mol) in THF wasintroduced. After 45 min. at room temperature (2S)(5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran (12.0g, 0.0357 mol) in THF (70 mL) was added at room temperature and stirredfor 3 h. (TLC, EtOAc-light petroleum 1:4, Rf=0.7). Saturated aqueousNH₄Cl solution was added at 0° C. to quench the reaction. THF wasremoved on rotavapor and the reaction mixture was partitioned betweenwater and EtOAc. The EtOAc layer was washed with water, brine, driedover Na₂SO₄ and concentrated to provide (2S)(5RS)-2-(4-fluorophenoxymethyl)-5-(4-tetrahydropyranoyl-1-butyne)tetrahydrofuran9, crude yield 18.9 g.

Part 3: (2S)(5RS)-2-(4-fluorophenoxy-methyl)-5-(4-hydroxybutyn-1-yl)tetrahydrofuran(Scheme V; 10)

That crude product 9 (18.9 g) was dissolved in methanol (60 mL) in 100mL round bottom flask fitted with magnetic stirring arrangement. 1% HClin methanol (25 mL) was introduced, and the reaction mixture was stirredat room temperature for 2 hours (TLC, EtOAc-light petroleum ether1:1,Rf=0.4). The reaction mixture was neutralized by saturated aqueousNa₂CO₃ solution and then concentrated under reduced pressure. Theresidue was extracted with ethyl acetate, washed with water, brine,dried over Na₂SO₄ and concentrated on rotavapor. The residue was driedunder vacuum on hot water bath to give (2S)(5RS)-2-(4-fluorophenoxy-methyl)-5-(4-hydroxybutyn-1-yl)tetrahydrofuran10, yield 10.9 g. HPLC analysis: Column ODS; flowrate: 1.0 mL/min.; UV:225 nm. Mobile phase 60% methanol in water. Trans:cis ratio (69:31).That crude product of 10 was crystallized (2 times) from ether-lightpetroleum ether by seeding to yield the pure product (3.3 g, 35%), m.p.76° C. [α]_(D)−34.26° (c 1.36, CHCl₃). HPLC purity above 95%.

EXAMPLE 5 Further Preparation of(4S)-4-fluorophenoxy-methyl)-γ-butyrolactone (Scheme VI; 6) Part 1:Trimethylene D-mannitol (Scheme VI; 16)

D-mannitol (2.0 kg, 10.98 mol) (Scheme VII; 15) formaldehyde solution(35% by weight, 4.4 lit, 51.2 mmol) and conc. HCl (4.0 lit.) were takenin a 10 lit. flask with mechanical stirring arrangement. The reactionmixture was kept at room temperature for 72 hours. The solid wasfiltered, washed with water and dried to provide 2.2 kg (91.9%) oftrimethylene D-mannitol 16, m.p. 228°-230°, [α]_(D)−108° (c 2.0, CHCl₃),TLC (silica gel), 1:2, ethyl acetate:hexane, Rf=0.4. ¹H NMR (CDCl₃): δ3.4-3.75 (m, 6H), 4.18 (dd, J=4.0, 8.0 Hz), 4.59 (d, 2H, J-4.0 Hz), 4.76(s, 2H), 5.05 (d, 2H, J=4.0 Hz).

Part 2: 1,3,4,6-Tetra-O-acetyl-2,5-O-methylene-D-mannitol (Scheme VI;17)

Ice cold acetylating mixture (10.1 lit.) prepared from 7.0 liters ofacetic anhydride, 3.0 liters of acetic acid and 0.1 liters ofconcentrated H₂SO₄ was taken in 20 lit. round bottom flask withmechanical stirring arrangement. Trimethylene D-mannitol 16 (2.2 kg,10.1 mol) was slowly added in portions (45 min.-1 hour). After 3 h thereaction mixture was poured over ice-water with vigorous stirring (50-60lit.). The solid was filtered, washed with water and dried to provide2.8 kg (78%) of 17, m.p. 126°-128°, [α]_(D)+57.8° (c 3.6, CHCl₃); TLC(silica gel), 2:1, ethyl acetate:hexane, Rf=0.5.

Part 3: 2,5-O-methylene-D-mannitol (Scheme VI; 18)

1,3,4,6-Tetra-O-acetyl-2,5-O-methylene-D-mannitol 17 (2.8 kg, 7.73 mol)was added to chloroform (14 lit.) in 25 lit. round bottom flask withmechanical stirring. The reaction mixture was cooled to 0° C., and 0.5%NaOMe solution (6.5 lit.) was added slowly. The reaction mixture wasstirred for 3 hours . The solid was filtered and dried to provide 1.0 kg(67%) of 2,5-O-methylene-D-mannitol 18, m.p. 172°-173° C., [α]_(D)−52°(c 1.18, CHCl₃), TLC (silica gel), 1:4, methanol:chloroform, Rf=0.8. ¹HNMR (D₂0): δ 3.42 (m, 2H), 3.72 (m, 4 H), 3.97 (m, 2 H), 4.91 (s, 2 H).

Part 4: 1,6-Di-O-tosyl-2,5-O-methylene-D-mannitol (Scheme VI; 19)

2,5-O-methylene-D-mannitol 18 (200 g, 1.03 mol) was dissolved inpyridine (1.2 lit.) in 3 liter two neck R B flask fitted with anaddition funnel and mechanical stirring arrangement. The reactionmixture was cooled to 0° C., tosyl chloride (430.9 g, 2.26 mol)dissolved in pyridine (0.8 lit.) was added slowly, and the reactionmixture was stirred a t room temperature for 12 h. Pyridine then wasremoved on rotavapour under vacuo. The thick slurry was poured overice-water (10 lit.) with mechanical stirring. After 2 hours the solidwas filtered, washed with water, dried (yield, 400 g crude) andcrystallized from methanol to provide 260 g of product 19, m.p. 142° C.,[α]_(D)−23.39° (c 1.7, MeCOMe), TLC (silica gel), 4:1, ethylacetate:hexane, Rf=0.4. ¹H NMR (CD₃COCD₃): δ 2.45 (s, 6H), 2.85 (s, 2H), 3.27 (m, 2 H), 3.65 (m, 2 H), 4.12 (dd, 2 H, J-6.2, 10.0 Hz), 4.45(m, 2 H), 4.46 (s, 2 H), 7.38, 7.63 (Abq, 8 H, J=8.0 Hz).

Part 5: 3,4-O-Ethoxymetyhlene-2,5-O-methylene-1-6-di-O-tosyl-D-mannitolScheme VI, 20)

2,5-O-methylene-1,6-di-O-tosyl-D-mannitol 19, (185 g, 0.368 mol)triethylorthoformate (613 mL) and PTSA (100 mg) were stirred in a 1 lit.round bottom flask fitted with mechanical stirring arrangement at roomtemperature. After 3 hours of stirring potassium carbonate was added toneutralize PTSA. Solid was filtered and filtrate concentrated underreduced pressure and dried under vacuo to provide 206 g (100%) ofproduct 20, m.p. 87-88° C., [α]_(D)+46.02° (c 0.93, CHCl₃), TLC (silicagel) 7:3 hexane:EtOAc, Rf=0.4. ¹H NMR (CDCl₃): δ 1.21 (t, 3 H, J=7.6Hz), 2.45 (s, 6 H), 3.55 (q, 2 H, J=7.6 Hz), 3.7-3.85 (m, 2 H), 3.97 (t,1 H, J=8.5 Hz), 4.08-4.31 (m, 5 H), 4.74 (s, 2 H), 5.76 (s, 1 H), 7.34,7.77 (ABq, 8 H, J=8.5 Hz).

Part 6:3,4-O-ethoxymethylene-1,6-di-O-p-fluorophenyl-2,5-O-methylene-D-mannitol(Scheme VI: 21)

4-Fluorophenol 2 (124 g, 1.107 mol) was dissolved in CH₃CN (250 mL) andthen KOH solution (62 g, in 45 mL, H₂O, 1.107 mol) was added. Thereaction mixture was stirred for 15 minutes.3,4-O-Ethoxymetyhylene-2,5-O-methylene-1-6-di-O-tosyl-D-mannitol 20 (206g, 0.369 mol) (used as prepared in Part 5 above without furtherpurification) in CH₃CN (400 mL) was separately taken in 1 liter two neckround bottom flask fitted with reflux condenser, guard tube andmechanical stirring arrangement. To this solution the potassium salt of4-fluorophenol was added at room temperature. The reaction mixture washeated under reflux for 6 hours and monitored by TLC (silica gel, 3:7,ethyl acetate:hexane, Rf=0.7). The reaction mixture was cooled inice-water and solid was filtered washed with ethyl acetate (100 mL), andthe combined filtrate was concentrated under reduced pressure. Theresulting residue was dissolved in ethyl acetate (800 mL) and theorganic layer was washed with 2M NaOH (4×100 mL), water and brine driedover Na₂SO₄. Concentration under reduced pressure afforded3,4-O-ethoxymethylene-1,6-di-O-p-fluorophenyl-2,5-O-methylene-D-mannitol21 (147 g, 90.9%). ¹H NMR (CDCl₃): δ 1.3 (t, 3 H, J=6.25 Hz), 3.70 (q, 2H, J=6.25 Hz), 4.0-4.45 (m, 7 H), 4.56 (t, 1 H, J=9.6 Hz), 5.19 (s, 2H), 5.97 (s, 1 H), 6.89-7.10 (m, 8 H).

Part 7: 1,6-Di-O-p-fluorophenyl-2,5-O-methylene-D-mannitol (Scheme VI:22)

3,4-O-Ethoxymethylene-1,6-di-O-p-fluorophenyl-2,5-O-methylene-D-mannitol 21 (145 g 0.331 mol),tetrahydrofuran (350 mL) and 0.1% aqueous HCl (40 mL) were mixed in a 1lit two neck round bottom flask fitted with mechanical stirringarrangement at 0° C. The reaction mixture was allowed to attain roomtemperature and further stirred for 6 hours and monitored by TLC (silicagel, 1:1, ethyl acetate:hexane, Rf=0.3). The reaction mixture wasbasified to pH 8 by saturated NaHCO₃ solution, and the solid wasfiltered and the filtrate concentrated to dryness to provide 125 kg(99%) of product 22, m.p. 126-127° C., [α]_(D)−34.49° (c 1.148, MeCOMe).¹H NMR (CDCl₃): δ 2.7 (s, 2 H), 3.72 (m, 2 H), 3.90 (m, 2 H), 4.12 (m, 4H), 4.87 (s, 2 H), 6.77-7.0 (m, 8 H).

Part 8: 4,4′-methylenedioxy-bis[(R)ethyl,(E)-2-ene-5-p-fluorophenoxypentanoate] (Scheme VI: 23)

In a 250 ml two neck round bottom flask equipped with magnetic stirringarrangement and fitted with a guard tube was taken a solution of1,6-di-O-p-fluorophenyl-2,5-O-methylene-D-mannitol 22 (10.0 g, 0.026mol) in CH₂Cl₂ (100 ml). The solution was cooled to 0° C. and Pb(OAc)₄(12.8 g, 0.0288 mol) was added in portions. After 3 hours, ethyleneglycol (1 ml) was added to quench excess Pb(OAc)₄. The reaction mixturewas filtered over celite, and the filtrate was washed successively withwater and brine. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to afford the di-aldehyde as a thicksyrup. That crude dialdehyde was taken in CH₂Cl₂ (100 ml) in 250 ml twonecked round bottom flask with magnetic stirring arrangement and fittedwith a nitrogen inlet. Carboethoxymethylenetriphenyl phosphorane (27.3g, 0.0785 mol) was added in portions. The reaction mixture then wasstirred for 3 hours, concentrated and purified on silica gelchromatography with 85:15 hexane:ethyl acetate as the eluent. Theisolated fractions on concentration under reduced pressure yielded4,4′-methylenedioxy-bis[ethyl, (E)-2-ene-5-p-fluorophenoxypentanoate] 23(10.0 g, 74%) as an oil. ¹H NMR (CDCl₃): δ 1.24-1.40 (m, 6 H), 3.86-4.30(m, 8 H), 4.70 (m, 1 H), 4.84 (s, 2 H), 5.70 (brs, 1 H), 5.9-6.32 (m, 4H), 6.76-7.02 (m, 8 H).

Part 9: 4S-(4-Fluorophenoxymethyl)-γ-butyrolactone (Scheme VI: 6)

A solution of 4,4′-methylenedioxy-bis[(R)ethyl,(E)-2-ene-5-p-fluorophenoxypentanoate] 23 (10.0 g, 0.0192 mol) inmethanol (10 ml) was taken in a 200 ml parr hydrogenation flask. Pd/C(500 mg) was added to that solution and the mixture shaken in a parrapparatus at 40-50 psi for 6 hour and monitored by TLC. The reactionmixture was filtered over celite and the filtrate concentrated to afford4,4′-methylenedioxy-bis[(R) ethyl, 5-p-fluorophenoxypentanoate] as anoil (10.0 g, 100%).

A 250 ml round bottom flask equipped with magnetic stirring arrangementand fitted with a reflux condenser was then charged with4,4′-methylenedioxy-bis [®ethyl, 5-p-fluorophenoxypentanoate] (10.0 g,0.019 mol) in ethanol (60 ml). To that solution 10% aqueous solutionH₂SO₄ (15 ml) was added. The mixture was heated under reflux for 10-12hours and monitored by TLC, silica gel, 1:1, ethyl acetate:hexane,Rf=0.25. The reaction was cooled to 0° C. and neutralized with saturatedsodium bicarbonate solution. The reaction mixture was concentrated on arotavapour to dryness and redissolved in ethyl acetate (100 ml). Theorganic layer was washed with water and brine dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography toafford off white crystalline solid of4S-(4-fluorophenoxymethyl)-γ-butyrolactone 6 (7.0 g, 87%), .m.p 60-61°C., [α]_(D)+25° (c 2.18, CHCl₃). ¹H NMR (CDCl₃): δ 2.13-2.80 (m, 4 H),4.02 (dd, 1 H, J=4.5, 9.0 Hz), 4.11 (dd, 1 H, J=4.5, 9.0 Hz), 4.80 (m, 1H), 6.75-7.02 (m, 4 H).

EXAMPLE 6 Further Alternate Preparation of (2S)(5RS)-2-(4-Fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran(Scheme VII; 10) Part 1: (±)-1,2-Epoxy-(4-fluoro)phenoxy propane (SchemeVII; 25)

p-Fluorophenol 2 (5 g, 44.6 mmol) and epichlorohydrin 24 (16.5 g, 178.4mmol 13) were admixed in anhydrous acetone (100 ml). Anhydrous K₂CO₃(24.0 g, 178.4 mmol) was added in 10 minutes and the reaction mixturewas heated at reflux for 18 hours until the complete consumption ofp-fluorophenol as monitored by TLC (4:1 hexane:ether). The reactionmixture then was filtered off, the filtrate was concentrated under vacuoto afford a light yellow oil, excess epichlorohydrin was distilled off,the residue was subjected to column chromatography on silica gel (2:8,ethyl acetate-hexane) to afford (±)-1,2-epoxy-(4-fluoro)phenoxy propane25 in quantitative yield (8.5 g).

Part 2: (2R)-3-(4-fluoro)phenoxy-propane-1,2-diol (Scheme VII; 26)

(2R)-3-(4-fluoro)phenoxy-propane-1,2-diol 26 was prepared usingJacobsen's catalyst as generally described in E. Jacobsen, Science,277:936-938 (1997). More specifically (±)-1,2-epoxy-3-(4-fluoro)phenoxypropane 25 (10 g, 59.5 mmol) and (R,R)-Jacobsen's catalyst (215 mg, 0.29mmol) were taken in a 50 ml round bottom flask and cooled to 0° C. Water(0.6 ml, 32.7 mmol) was then added dropwise for 1 hour and stirred for 5hours at room temperature, monitored by TLC (1:1 ethyl acetate:hexane).Ethyl acetate (50 ml) was added, followed by anhydrous Na₂SO₄ (200 mg),stirred for 10 minutes filtered, concentrated to afford dark coloredresidue of a mixture of 26 and 27, which on column chromatography gaveisolated epoxide 27 (4.36 g, 43%, 1:9 ethyl acetate-hexane) and(2R)-3-(4-fluoro)phenoxy-propane-1,2-diol 26 (5.06 g, 46%, 1:1 ethylacetate-hexane).

Part 3: (2S)-3-(4-fluoro)phenoxy-1-tosyloxy-propan-2-ol (Scheme VII; 28)

A mixture of (2R)-3-(4-fluoro)phenoxy-propan-1,2-diol 26 (5.0 g, 26.8mmol) and pyridine (4.5 ml) in CH₂Cl₂ (60 ml) were cooled to 0° C., andthen p-toluenesulphonyl chloride (5.0 g, 26.8 mmol) was added portionwise to the cooled mixture. The mixture was stirred at room temperatureovernight (TLC 2:3, ethyl acetate-hexane). The solvent was then removedby codistillation with toluene, and the resulting residue purified bysilica gel column chromatography (2:3, ethyl acetate-hexane) to affordthe product 28 (7.7 g, 85%).

Part 4: (2R)-1,2-epoxy-3-(4-fluoro)phenoxypropane (Scheme VII; 4)

(2R)-(4-Fluoro)phenoxy-1-tosyloxy-propan-2-ol 28 (5.0 g, 14.7 mmol) in asolvent mixture of THF and DMF (100 ml, 4:1) was cooled to 0° C. and NaH(0.75 g, 19.2 mmol) was added portionwise, followed by stirring of thereaction mixture for 1 hour at room temperature with monitoring of thereaction by TLC (20% ethyl acetate in hexane). The THF was removed andthe residue was taken in ethyl ether (50 ml). That ether solution waswashed successively with water (3×50 ml), brine (1×50 ml) dried (Na₂SO₄)and concentrated to afford (2R)-1,2-epoxy-3-(4-fluoro)phenoxypropane 4as a colorless oil (2.53 g, 95%).

Part 5: (2R)-1-(4-fluoro)phenoxyhex-5-en-2-ol (Scheme VII; 29)

Magnesium (0.89 g, 36.6 mmol) and iodine (catalytic amount) were takenin a 50 ml 2-neck round bottom flask provided with a reflux condenserand a septum, under N₂ atmosphere. A solution of allyl bromide (3.0 g,24.4 mmol) in 10 ml of ethyl ether was slowly added and stirred for 30minutes at room temperature. Cuprous cyanide (22 mg) then was added, andthe color of the reaction mixture became dark brown. The reactionmixture was cooled to −22° C. (CCl₄/dry ice bath), and(2R)-1,2-epoxy-3-(4-fluoro)phenoxypropane 4 (2.05 g, 12.2 mmol) in 25 mlof ethyl ether was added. The reaction was completed within 30 minutes,as determined by TLC (benzene). Saturated aqueous ammonium chloride (4ml) then was added and the mixture stirred for 30 minutes. Inorganicmaterial was filtered and washed with ethyl ether (25 ml). The etherlayer was dried (sodium sulphate) concentrated to give a colorless oilof (2R)-1-(4-fluoro)phenoxyhex-5-en-2-ol 29 (2.3 g, 90%).

Part 6: (2R)-2-benzenesulfonyloxy-1-(4-fluoro)-phenoxy-5-hexane (SchemeVII; 30)

(2R)-(4-Fluoro)phenoxyhex-5-en-2-ol, 29 (7.4 g, 35.2 mmol),triethylamine (10 ml) and 4-N,N′-dimethylaminopyridine (DMAP, 0.43 g,catalytic) were dissolved in 50 ml of dry CH₂Cl₂ and cooled in ice bathwhile stirring. Benzenesulfonyl chloride (5 ml, 38.7 mmol) in CH₂Cl₂ (10ml) was then added dropwise to the mixture. The reaction mixture wasstirred at room temperature for 6 hours and monitored by TLC (benzene)].Solvent then was removed and the residue was poured onto a short silicagel column and eluted with 1:4 ethyl acetate-hexane to afford(2R)-2-benzenesulfonyloxy-1-(4-fluoro)-phenoxy-5-hexane 30 as acolorless oil (11.3 g, 92%).

Part 7:(6R,2E)-ethyl-6-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-oate(Scheme VII; 31)

(2R)-2-Berzenesulfonyloxy-1-(4-fluoro)-phenoxy-5-hexane 30 (11.3 g, 32.5mmol 19) in 30 ml of dry CH₂Cl₂ was cooled to −78° C. O₃ then wasbubbled through the mixture until the blue color persisted (30 minutes).A stream of N₂ then was purged for 5 minutes through the mixture toremove excess of ozone. Dimethylsulfide (13.9 ml, 325 mmol) was addedand stirred for 2 hours. The reaction mixture was washed with water(2×25 ml), brine (1×30 ml) and concentrated to afford the crude product(10.8 g, 95%). (2R)-Benzenesulfonyloxy-1-(4-fluoro)-phenoxy-5-pentanal(10.5 g, 30 mmol) was added and heated at reflux for 5 hours.Ethoxycarbonylmethylene triphenylphosphorane (11.5 g, 33 mmol) was addedand heated at reflux for 5 hours. Completion of the reaction was checkedby TLC (1:10, EtOAc-benzene) and the solvent was removed, the residuewas purified by column chromatography on silica gel (1:3, ethylacetate-hexane) to afford(6R,2E)-ethyl-6-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-oate31 (8.8 g, 70%) as a colorless oil.

Part 8:(6R,2E)-ethyl-6-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-ol(Scheme VII; 32)

(6R,2E)-Ethyl-6-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-oate(3 g, 7.1 mmol) 31 was dissolved in 30 ml of CH₂Cl₂ under N₂ atmosphereand cooled to −78° C. DIBAL-H (14.2 ml, 14.2 mmol, 1M solution intoluene) was added dropwise over 5 minutes and the solution was stirredat −78° C. for 45 minutes. At reaction completion as monitored by TLC(2:5, ethyl acetate-hexane), saturated aqueous ammonium chloridesolution (3 ml) was added and the mixture stirred for another 30minutes. The reaction mixture then was filtered through a celite pad thefiltrate was dried over anhydrous Na₂SO₄ and concentrated, the residuewas filtered through a short silica gel pad and concentrated to obtain(6R,2E)-ethyl-6-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-ol32 as a solid (2.2 g, 82% yield).

Part 9:(2S,3S,6R)-6-benzenesulfonyloxy-2,3-epoxy-7-(4-fluoro)-phenoxy-7-heptan-1-ol(Scheme VII; 33)

Powdered molecular sieves 4 Å (3 g) were activated under N₂ atmospherein a 25 ml 2 necked round bottom flask. CH₂Cl₂ (15 ml) was addedfollowed by titanium tetraisopropoxide (1.62 ml, 5.47 mmol),(+)-diisopropyltartrate (1.07 ml, 6.56 mmol) and the mixture was cooledto −20° C. with stirring. After 5 minutes cumene-hydroperoxide (2.1 ml,10.94 mmol, 80% solution in cumene) was added dropwise. The mixture wasstirred for 15 minutes at −20° C.(6R,2E)-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-ol 32 (2.0g, 5.47 mmol) in 10 ml of CH₂Cl₂ was then added and the reaction mixturewas stirred for 2.5 hours at −20° C. The reaction mixture was checkedfor the completion by TLC (1:1, ethyl acetate-hexane), 1 ml of 10%aqueous tartaric acid solution was added at −20° C. and the reactionmixture was warmed to room temperature in 30 minutes. The reactionmixture was filtered through a celite pad dried over Na₂SO₄,concentrated and the residue was subjected to column chromatography onsilica gel (1:1, ethyl acetate-hexane) to afford(2S,3S,6R)-6-benzenesulfonyloxy-2,3-epoxy-7-(4-fluoro)-phenoxy-7-heptan-1-ol33 (2.4 g, 98% yield) as a solid.

Part 10:(2S,3S,6R)-6-benzenesulfonyloxy-1-chloro-2,3-epoxy-7-(4-fluoro)-phenoxy-heptane(Scheme VII; 34)

(2S,3S,6R)-6-Benzenesulfonyloxy-2,3-epoxy-7-(4-fluoro)-phenoxy-7-heptan-1-ol(2.25 g, 5.7 mmol) 33 and triphenylphosphine (1.5 g, 5.7 mmol) weredissolved in solvent mixture of CHCl₃ and CCl₄ (40 ml, 1:1) and NaHCO₃(0.3 g) was added. The reaction mixture was refluxed for 3 hours andmonitored by TLC (2:5, ethyl acetate-hexane). Solvent was removed, theresidue was purified by column chromatography on silica gel (1:4, ethylacetate-hexane) to afford(2S,3S,6R)-6-benzenesulfonyloxy-1-chloro-2,3-epoxy-7-(4-fluoro)-phenoxy-heptane34 (1.5 g, 64% yield) as a solid.

Part 11: (2S,5S)-5-ethynyl-2-(4-fluoro)-phenoxymethyl-tetrahydrofuran(Scheme VII; 35)

n-BuLi (7.2 ml, 7.2 mmol) was added to a solution of freshly distilleddiisopropylamine (1.12 ml, 8.6 mmol) in 6 ml of dry THF at −40° C. andstirred for 15 minutes. A solution of(2S,3S,6R)-6-benzenesulfonyloxy-1-chloro-2,3-epoxy-7-(4-fluoro)-phenoxy-heptane34 (1.0 g, 2.42 mmol) was added in 8 ml of dry THF. The reaction mixturewas stirred at −40° C. for 1 hour and then at room temperature for 1hour. When TLC showed complete consumption of starting material thereaction was quenched at 40° C. with aqueous ammonium chloride (1 ml),THF was removed under vacuo, the residue was taken in ethyl acetate,filtered, dried over Na₂SO₄ and concentrated. Crude product wassubjected to column chromatography on silica gel (1:9, ethylacetate-hexane) to afford(2S,5S)-5-ethynyl-2-(4-fluoro)-phenoxymethyl-tetrahydrofuran 35 (0.32 g,60% yield).

Part 12: Preparation of(2S,5S)-5-(2′-hydroxyethyl)-ethynyl-2-(4-fluoro)-phenoxymethyltetrahydrofuran(Scheme VII; 10)

To a solution of(2S,5S)-5-ethynyl-2-(4-fluoro)-phenoxymethyl-tetrahydrofuran 35 (0.8 g,3.6 mmol) in 15 ml of dry THF at −78° C., n-BuLi (5 ml, 1M solution inhexane), stirred for 15 minutes. Freshly distilled BF₃Et₂O (1.4 ml, 11mmol) was added followed by ethyleneoxide (excess, THF solution). Thereaction mixture was continued to stir at −78° C. until completion (30minutes). Saturated aqueous ammonium chloride solution (1 ml) was addedat −78° C. stirred for 5 minutes, warmed to room temperature, THF wasremoved, residue was extracted with ether (2×20 ml), combined organiclayer was dried over Na₂SO₄, concentrated to afford a residue. Thatresidue was purified by column chromatography on silica gel (2:5, ethylacetate-hexane) to afford(2S,55)-5-(2′-hydroxyethyl)-ethynyl-2-(4-fluoro)-phenoxymethyltetrahydrofuhran10 (0.87 g, 90% yield) as a white solid. That product 10 was found to beidentical (NMR, optical rotation, TLC) with samples prepared by Example1 above.

Example 7 Preparation of(±)-2-(4-Fluorophenoxymethyl)-7-(4-N-hydroxy-ureidyl-1-butynyl)-oxepane(Scheme VIII; 42) Part 1: (±)-7-Benzyloxy-1-(fuorophenoxy)-heptane-2-ol(Scheme VIII; 42)

Magnesium (2.4 g, 98 mmol) was added to a 250 ml flask and flame dried.Dry THF, 25 ml, and 1 ml of dibromoethane were then added.1-Bromo-4-benzyloxy-butane 41 (12 g, 49.4 mmol) dissolved in 50 ml ofdry THF was added dropwise and the reaction mixture was stirred at roomtemperature. After 1 hour, the reaction mixture is cooled in anice-water bath and 90 mg of copper cyanide is added. After 10 minutes inan ice-bath, 4-fluorophenyl-glycidyl ether (5 g, 29.6 mmol) dissolved in30 ml of dry THF is added slowly. The reaction is monitored by TLC(ethyl acetate:hexane 3:7). After 15 minutes, the reaction is quenchedwith saturated aqueous ammonium chloride, concentrated and partitionedbetween water-ethyl acetate. The ethyl acetate layer is then washed withbrine, dried over Na₂SO₄ and concentrated to give the desiredbenzyloxy-heptane 42. The structure was confirmed by ¹H-NMR.

Part 2: (±)-7-(4-Fluorophenoxy)-6-(2-methoxyethoxymethoxy)-heptane-1-ol(Scheme VIII, 43)

(±)-7-Benzyloxy-1-(fluorophenoxy)-heptane-2-ol 42 (9.8 g, 29.5 mmol) in30 ml of chloroform is added to a 100 ml round bottom flask.Diisopropylethylamine (7.6 ml, 44.3 mmol) and methoxyethoxymethylchloride (3.7 ml, 32.5 mmol) are added and the reaction mixture isstirred for 3 hours. The mixture is then washed with water, brine, dried(Na₂SO₄) and concentrated. The residue was purified on silica gel (ethylacetate:hexane 1:9) to give(±)-7-benzyloxy-1-(4-fluorophenoxy)-2-(2-methoxyethoxymethoxy)-heptane7-3 (11 g, 89%).

Part 3: (±)-7-(4-Fluorophenoxy)-6-(2-methoxyethoxymethoxy)heptan-1-ol(Scheme VIII; 44)

(±)-7-benzyloxy-1-(4-fluorophenoxy)-2-(2-methoxyethoxy-methoxy)-heptane43 (11 g, 26.3 mmol) in 30 ml of ethanol is added to a 50 ml roundbottom flask. Palladium on activated carbon (10% Pd/C, 150 mg) is addedand the reaction mixture is stirred under an atmosphere of hydrogen.After 3 hours, the reaction mixture was filtered through celite, washedwith ethanol and concentrated. The crude product was purified on silicagel (ethyl acetate:hexane 1:1) to give(±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)heptan-1-ol 44 (7.9g,91%). The structure was confirmed by ¹H-NMR.

Part 4: (±)-7-(4-Fluorophenoxy)-6-(2-methoxyethoxymethoxy)-heptan-1-al(Scheme VIII; 45)

Oxalyl chloride (2.9 ml, 33.6 mmol) is added to 25 ml of methylenechloride and cooled to −78° C. Dry dimethyl sulfoxide (4.7 ml, 67.2mmol) is then added and the reaction is stirred at −78° C. After 45minutes, (±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)-heptan-1-ol44 (3.7 g, 11.2 mmol) dissolved in CH₂Cl₂ is added and the reaction isstirred at −78° C. After 1 hour, the reaction is quenched with 15.7 mlof triethylamine and diluted with CH₂Cl₂. The reaction mixture is thenwashed with water, brine dried (Na₂SO₄) and concentrated. The crudeproduct is purified on silica gel (ethyl acetate:hexane 1:9) to give(±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)-heptan-1-al 45, 3.3g, 89%.

Part 5: (±)-7-(4-fluorophenoxy)-6-(hydroxy)-heptan-al (Scheme IX; 47)

(±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)heptan-1-al 45 (2 g,6.1 mmol) and 2 ml of trifluoroacetic acid are added to 10 ml ofchloroform. The reaction mixture is stirred for 24 hours and then isneutralized with 1% aqueous NaOH. The organic layer is washed withwater, brine, dried (Na₂SO₄), concentrated. The crudetrifluoroacetyl-aldehyde 46 is then dissolved in MeOH:H₂O (1:1) andsolid K₂CO₃ is added to maintain pH 8. The reaction is complete isapproximately 15 minutes, as monitored by TLC (ethyl acetate:hexane3:7). Methanol is removed in vacuo and remaining solution is extractedwith ethyl acetate to give (±)-7-(4-fluorophenoxy)-6-(hydroxy)-heptan-al47 (1.2 g, 82%).

Part 6: (±)-7-(Benzylsulfonyl)-(4-fluorophenopxymethyl)-oxepane (SchemeIX; 48)

Benzene sulfinic acid (0.79 g, 5.62 mmol) and CaCl₂ (0.62 g, 5.62 mmol)are added to 15 ml of CH₂Cl₂ and cooled in an ice-water bath.(±)-7-(4-Fluorophenoxy)-6-(hydroxy)heptan-1-al 47 (0.90 g, 3.75 mmol),dissolved in 5 ml of CH₂Cl₂, is added to the reaction mixture andstirred at room temperature. After 3 hours the reaction mixture isfiltered through celite and washed with CH₂Cl₂. The filtrate is washedwith saturated aqueous Na₂CO₃, water, brine, dried (Na₂SO₄) andconcentrated. The crude product is then purified on silica gel (ethylacetate:hexane 1:6) to give(±)-7-(benzylsulfonyl)-(4-fluorophenopxymethyl)-oxepane 48 in 80% yield(1.1 g). The structure was confirmed by ¹H-NMR.

Part 7:(±)-2-(4-Fluorophenoxymethyl)-7-(tetrahyropyranyloxybutyn-1-yl)-oxepane(Scheme IX; 49)

Magnesium (0.1 g, 4.3 mmol) was added to a 50 ml round bottom flask andflame dried. Dry THF (10 ml) and a few drops of 1,2-dibromoethane werethen added followed by isopropyl bromide (0.34 g, 2.7 mmol). Thereaction was stirred for 1 hour and the resulting isopropyl magnesiumbromide solution was cannulated into a 100 ml flame dried flask.4-Tetrahydropyranoyl-1-butyne (0.34 g, 2.18 mmol) dissolved in THF wasadded to the reaction mixture and it was stirred. After 30 minutes, thereaction mixture was cooled in an ice-water bath and ZnBr₂ (1.3 ml, 1 Min THF) was added at room temperature. After 45 minutes,(±)-7-(benzensulfonyl)-2-(4-fluorophenoxymethyl)-oxepane (0.4 g, 1.1mmol) dissolved in 2 ml of THF was added. The reaction was stirred atroom temperature for 30 minutes, then cooled in an ice-water bath andthe reaction was quenched with saturated aqueous NH₄Cl. THF was removedin vacuo and the reaction mixture was partitioned between water andethyl acetate. The ethyl acetate layer was washed with water, brine,dried (Na₂SO₄) and concentrated to get(±)-2-(4-fluorophenoxymethyl)-7-(4-teterahydropyranyloxybutyn-1-yl)-oxepane49 which was used with out further purification.

Part 8: (±)-2-(4-Fluorophenoxymethyl)-7-(4-hydroxybutyn-1-yl)-oxepane(Scheme X; 50)

(±)-2-(4-Fluorophenoxymethyl)-7-(4-teterahydropyranyloxybutyn-1-yl)-oxepane49 from the above reaction was dissolved in 5 ml of methanol and 2 ml of1% HCl in methanol was added. Hydrolysis of the THP group was completein 2 hours as detected by TLC (ethyl acetate:hexane 4:6). The reactionmixture was neutralized by addition of solid Na₂CO₃ and solvent wasevaporated. The residue was dissolved in ethyl acetate, washed withwater, brine, dried (Na₂SO₄) and concentrated. The crude product waspurified on silica gel (ethyl acetate:hexane 3:7) to give(±)-2-(4-fluorophenoxymetyl)-7-(4-hydroxybutyn-1-yl)-oxepane 50 (0.24 g,75%). The product was confirmed by ¹H-NMR.

Part 9:(±)-2-(4-Fluorophenoxymethyl)-7-[4-(N,O-biscarbo-henoxy)-1-butynyl]-oxepane(Scheme X; 51)

A solution of(±)-2-(4-fluorophenoxymetyl)-7-(4-hydroxybutyn-1-yl)-oxepane 50 (0.12 g,0.41 mmol) and 5 ml of dry THF was cooled in an ice-water bath.Triphenylphosphine (0.13 g, 0.49 mmol),N,O-biscarbophenoxy-hydroxylamine (0.135 g, 0.49 mmol) and diethylazodicarboxylate (0.85 g, 0.49 mmol) were then added sequentially. Thereaction mixture was stirred at room temperature. After 4 hours, solventwas in vacuo and the residue was dissolved in ethyl acetate, washed withwater, brine, dried (Na₂SO₄) and concentrated. The residue was purifiedon silica gel (ethyl acetate:hexane 6:1) to give(±)-2-(4-fluorophenoxymethyl)-7-[4-N,O-biscarbo-henoxy)-butynyl]-oxepane51 in 92% yield (0.195 g). The structure was confirmed by ¹H-NMR.

Part 10:(±)-2-(4-Fluorophenoxymethyl)-7-(4-N-hydroxy-ureidyl-1-butynyl)-oxepane(Scheme X; 52)

(±)-2-(4-Fluorophenoxymethyl)-7-[4-N,O-biscarbo-henoxy)-butynyl]-oxepane51 was dissolved in 10 ml of methanol and 2 ml of a saturated solutionof ammonia in methanol was added. The reaction mixture was stirred atroom temperature. After 12 hours the solvent was removed and the crudeproduct was purified on silica gel (ethyl acetate:hexane 1:1) to give(±)-2-(4-fluorophenoxymethyl)-7-(4-N-hydroxy-ureidyl-1-butynyl)-oxepane52 in 82% yield (55 mg). The structure was confirmed by ¹H-NMR.

Example 8 Preparation of (2RS,6S)-2-Benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran

References in this Example 8 to compound numerals (generally underlined)designate the compounds depicted structurally in the following SchemeXIX:

Part 1: (S)-Glycidyl-4-fluorophenyl ether (Scheme XIX; 3):

To a solution of 4-fluorophenol (40 g, 0.35 mol) in acetone (350 ml) wasadded dry K₂CO₃ (148 g, 1.05 mol) and epichlorohydrin (95 ml, 1.05 mol).The reaction mixture was heated at 60° C. for 12 h, then filtered andthe filtrate distilled under reduced pressure (b.p. 160-170° C./9 mm) toafford pure (R,S)-glycidyl-4-fluorophenyl ether (52 g, 85%) as acolourless liquid. Co-salen acetate (RR-catalyst) (1.03 g, 1.54 mmol)was added to (R,S)-glycidyl-4-fluorophenyl ether (52 g, 0.3 mol),followed by drop wise addition of water (3.06 ml, 0.17 mol) over 1 h at0° C. The reaction mixture was allowed to come to room temperature andstirred for 18 h. The catalyst was filtered off and the filtratedistilled under reduced pressure to afford (S)-glycidyl-4-fluorophenylether (22 g, 85%) as a colourless liquid. TLC: ethyl acetate-lightpetroleum (1:4), Rf=0.5. Boiling point: 160-170° C./9 mm. Opticalrotation [α]_(D): +5° (c 2.3, CHCl₃). ¹H NMR (CDCl₃, 200 MHz) δ 2.68(dd, J=4.5, 2.2 Hz, 1H), 2.85 (t, J=4.5 Hz,1H), 3.27 (m, 1H), 3.89 (dd,J=15.7, 6.7 Hz, 1H), 4.11 (dd, J=15.7, 4.5 Hz, 1H), 6.74-7.02 (m, 4H).

Part 2: Methyl (S)-6-(4-fluorophenoxy)-5-hydroxy-hex-2-ynoate (SchemeXIX; 4)

A solution of n-BuLi in hexane (11.4 ml, 26.8 mmol) was added at −78° C.to a solution of methyl propiolate (2.25 g, 26.8 mmol) in THF (15 ml)under N₂ atmosphere and the mixture was stirred for 20 min.Borontrifluoride etherate (3.4 ml, 26.8 mmol) was then added to thesolution, stirring was continued for a further 20 min at −78° C. Asolution of (S)-glycidyl-4-fluorophenyl ether (3 g, 17.8 mmol) in THF(10 ml) was then added and after stirring for 1 h at −78° C., thereaction was quenched by the addition of aqueous NH₄Cl. The reactionmixture was extracted with ethylacetate, dried (Na₂SO₄), andconcentrated. The crude product was purified on a silica gel(EtOAc-light petroleum (1:4) as eluent) to afford methyl(S)-6-(4-fluorophenoxy)-5-hydroxy hex-2-ynoate (2.5 g, 60%) as a yellowcolour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. Opticalrotation [α]_(D): +15.5° (c 1.2, CHCl₃). ¹H NMR (CDCl₃, 200 MHz): δ 2.62(d, J=5 Hz, 1H), 2.71 (d, J=5.6 Hz, 2H), 3.76 (s, 3H), 3.92-4.02 (m,2H), 4.2 (m, 1H), 6.8-7.02 (m, 4H).

Part 3: Methyl (S)-6-(4-fluorophenoxy)-5-hydroxy-hexanoate (Scheme XIX;5)

To a solution of methyl (S)-6-(4-fluorophenoxy)-5-hydroxy hex-2-ynoate(2.5 g, 9.9 mmol) in methanol (20 ml), 10% Pd/C (250 mg) was added andthe mixture stirred under H₂ at room temperature for 3 h. The reactionmixture was filtered through celite, washed with methanol andconcentrated in vacuum. The residue was purified on silica gel columnusing EtOAc-light petroleum (1:4) to give methyl(S)-6-(4-fluorophenoxy)-5-hydroxy-hexanoate (2.15 g, 85%) as acolourless liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4.Optical rotation [α]_(D): +8° (c 1.1, CHCl₃). ¹H NMR (CDCl₃, 200 MHz): δ1.55-1.9 (m, 4H), 2.3-2.43 (t, J=6.5 Hz, 2H), 2.5 (s, 1H), 3.68 (s, 3H),3.76-4.02 (m, 3H), 6.76-7.02 (m, 4H).

Part 4: (6S)-6-(4-Fluorophenoxymethyl)-tetrahydropyran-2-one (SchemeXIX; 6)

To a solution of methyl (S)-6-(4-fluorophenoxy)-5-hydroxy-hexanoate (0.8g 3.12 mmol) in CH₂Cl₂ (20 ml), a catalytic amount of PTSA (10 mg) wasadded and the reaction mixture was stirred at 40° C. for 12 h. Thereaction was then neutralised with sodium bicarbonate and the productextracted with dichloromethane. The organic layer was dried (Na₂SO₄) andconcentrated. The crude product on purification on a silica gel(EtOAc-light petroleum (1:3) as eluent) gave(6S)-6-(4-fluorophenoxymethyl)-tetrahydropyran-2-one (0.5 g, 70%) as acolourless liquid. TLC:ethyl acetate-light petroleum (1:4), Rf=0.3.Optical rotation [α]_(D): +19° (c 0.9, CHCl₃). ¹H NMR (CDCl₃, 200 MHz):δ 1.7-2.15 (m, 4H), 2.48-2.7 (m, 2H), 3.95-4.15 (m, 2H), 4.55-4.7 (m,1H), 6.77-7.0 (m, 4H).

Part 5:(2RS,6S)-2-Benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran(Scheme XIX; 8):

To solution of (6S)-6-(4-fluorophenoxymethyl)-tetrahydropyran-2-one (0.5g, 2.23 mmol) in dry CH₂Cl₂ was added DIBAL-H (1 ml, 2M solution intoluene, 2.4 mmol) dropwise at −78° C. The reaction mixture was stirredat −78° C. for 3 h. It was then quenched with potassium sodium tartrate,extracted with dichloromethane, dried (Na₂SO₄), and concentrated toafford the crude product (0.42 g, 85%).

25% HCl was added dropwise to benzenesulfinic acid sodium salt (0.6 g),until the solid dissolved. This mixture was extracted with ethyl acetate(5 ml) dried (Na₂SO₄) and concentrated to give benzenesulfinic acid (0.4g). To an ice-cooled mixture of benzenesulfinic acid (0.32 g, 2.23 mmol)and calcium chloride (0.25 g, 2.23 mmol) in dry CH₂Cl₂ a solution of(2RS, 6S)-6-(4-fluorophenoxymethyl)-2-hydroxy-tetrahydropyran (0.42 g,1.86 mmol) in dry CH₂Cl₂ (5 ml) was added. The reaction mixture wasstirred for 4 h, filtered through celite and washed with CH₂Cl₂. Thecombined organic layers were washed with saturated aqueous Na₂CO₃,water, brine and dried (Na₂SO₄). The solvent was removed under vacuumand the residue was purified on a silica gel column using lightpetroleum-ethyl acetate (4:1) as eluent to afford pure (2RS,6S)-2-benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g,70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3),Rf=0.4. ¹H NMR (CDCl₃, 200 MHz): δ 1.5 (m, 2H), 1.75-2.0 (m, 2H),2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H),4.85-5.0 (m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz,2H).

Example 9 Preparation of (2S,6S)-6-(4-Fluorophenoxymethyl)-2-(4-N-hydroxyureidyl-1-butynyl)-tetrahydropyran(Scheme XX; 17)

References in this Example 9 to compound numerals (generally underlined)designate the compounds depicted structurally in the following SchemeXX:

Part 1: (2S)-6-Benzoloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (Scheme XX;9):

To a solution of benzyloxy prop-2-yne (2.3 g, 16 mmol) in dry THF (25 ml) at −78° C. was added n-BuLi in hexane (10.7 ml 16 mmol) and themixture stirred for 20 min. Borontrifluoride etherate (2 ml , 16 mmol)was then added to the solution and stirring continued for 20 min. at−78° C. A THF solution of (S)-glycidol-4-fluorophenyl ether (1.8 g, 10.7mmol) was added and after stirring for 1 h at −78° C., the reaction wasquenched by adding aqueous NH₄Cl. The organic materials were extractedwith ethyl acetate, dried (Na₂SO₄) and concentrated under vacuum. Thecrude product was purified on a silica gel column using EtOAc-lightpetroleum (1:4) as eluent to give(2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 65%) as ayellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4.¹H NMR (CDCl₃, 200 MHz): δ 2.65 (m, 2H), 3.95-4.10 (m, 2H), 4.13-4.21(m, 3H), 4.6 (s, 2H), 6.8-7.02 (m, 4H), 7.30-7.38 (m, 5H).

Part 2:(2S)-6-Benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne(Scheme XX; 10)

To an ice cooled solution of(2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 6.4 mmol) indry CH₂Cl₂ (8 ml) was added N-ethyldiisopropylamine (1.7 ml, 9.5 mmol)and stirred for 10 minutes MEM-chloride (1.1 ml, 9.5 mmol) was added tothe solution at 0° C. and stirred for 3 h at room temperature. Thesolvent was concentrated and the residue purified on a silica gel columnusing EtOAc-light petroleum (1:4) as eluent to yield(2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne(2.2 g, 85%) as a yellow colour liquid. TLC:ethyl acetate-lightpetroleum (1:3), Rf=0.5 ¹H NMR (CDCl₃, 200 MHz): δ 2.65-2.75 (m, 2H),3.39 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 3.78 (t, J=4.8 Hz, 2H), 4.11 (s,2H), 4.16 (m, 3H), 4.56 (s, 2H), 4.89 (s, 2H), 6.8-7.02 (m, 4H),7.3-7.35 (m, 5H).

Part 3: (2S)-1-(4-Fluorophenoxy)-2-(methoxyethoxymethyloxy)-hexan-6-ol(Scheme XX; 11)

To a solution of(2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne(2.2 g, 5.4 mmol) in dry methanol (20 ml) was added 10% Pd/C (250 mg)and the mixture stirred under H₂ at room temperature for 4 h. Thereaction mixture was filtered through celite, washed with excessmethanol. Evaporation of the solvent afforded a crude product which waspurified by silica gel column using ethyl acetate-light petroleum (2:3)as eluent to give(2S)-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hexan-6-ol (1.3 g,76%) as a colourless liquid. TLC:ethyl acetate-light petroleum (2.3),Rf=0.3. ¹H NMR (CDCl₃, 200 MHz) δ 1.5-1.7 (m, 6H), 3.35 (s, 3H), 3.5 (t,J=4.8 Hz, 2H), 3.65 (t, J=4.8 Hz, 2H) 3.7-3.8 (m, 2H), 3.85-3.95 (s,3H), 4.75-4.95 (dd, J=12.6, 6.0 Hz, 2H), 6.75-7.0 (m, 4H).

Part 4: (2RS, 6S)-6-(4-Fluorophenoxymethyl)-2-methoxy-tetrahydropyran(Scheme XX; 13)

To a solution of(2S)-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hexan-6-ol (1.25 g,3.9 mmol) and oxalyl chloride (0.7 ml, 7.9 mmol) in dry CH₂Cl₂ was addeddry DMSO (1.12 ml, 15.8 mmol) slowly at −78° C. The stirring wascontinued for a further 30 min. at −78° C. and quenched with dry Et₃N(3.15 ml, 23.7 mmol). The reaction mixture was extracted with CH₂Cl₂ anddried (Na₂SO₄) to afford the crude aldehyde (1.1 g, 85%). A 20%methanolic HCl solution was added to the aldehyd and stirred for 5 h. atroom temperature. The reaction mixture was neutralised with aqueousNaHCO₃, extracted with ethyl acetate, dried (Na₂SO₄) and concentratedunder vacuum. The crude product was purified by silica gel columnchromatography to give a cis-trans mixture (2RS,6S)-6-(4-fluorophenoxymethyl)-2-methoxytetrahydropyran (0.6 g, 80%) as ayellow syrup. TLC:ethyl acetate-light petroleum (1:3), Rf=0.8. ¹H NMR(CDCl₃, 200 MHz): δ 1.6-2.0 (m, 6H), 3.45 (s, 3H), 3.9-3.96 (m, 2H),4.0-4.15(m, 1H), 4.8 (s, 1H), 6.8-7.01 (m, 4H).

Part 5: (2RS,6S)-2-Benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran (SchemeXX; 8)

25% HCl was added dropwise to benzenesulfinic acid sodium salt (2.0 g),till the solid dissolved. This mixture was extracted with ethyl acetate(30 ml), dried (Na₂SO₄) and concentrated to give benzenesulfinic acid(1.5 g). To an ice-cooled mixture of benzenesulfinic acid (1.48 g, 10.5mmol) and calcium chloride (1.15 g, 10.5 mmol) in dry CH₂Cl₂ a solutionof (2RS, 6S)-6-(4-fluorophenoxymethyl)-2-methoxytetrahydropyran (0.5 g,2.1 mmol) in dry CH₂Cl₂ (5 ml) was added. The reaction mixture wasstirred for 4 h, filtered through celite and washed with CH₂Cl₂. Thecombined organic layer was washed with saturated aqueous Na₂CO₃, water,brine and dried (Na₂SO₄). The solvent was removed under vacuum and theresidue was purified on a silica gel column using light petroleum-ethylacetate (4:1) as eluent to afford pure (2RS,6S)-6-benzenesulfonyl-2-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g,70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3),Rf=0.4. ¹H NMR (CDCl₃, 200 MHz): δ 1.5 (m, 2H), 1.75-2.0 (m, 2H),2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H)4.85-5.0 (m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz,2H).

Part 6:(2S,6S)-6-(4-Fluorophenoxymethyl)-2-(4-hydroxybutyn-1-y)-tetrahydropyran(Scheme XX; 15)

To a suspension of magnesium (0.14 g, 5.7 mmol) in dry THF (5 ml)catalytic 1,2-dibromoethane was added followed by dropwise addition of asolution of isopropylbromide (0.3 ml, 2.86 mmol) in THF. The reactionmixture was stirred for 1 h and the isopropylmagnesiumbromide wascannulated into a two necked flask. A solution4-tetrahydropyranoyl-1-butyne (0.44 g, 2.86 mmol) in THF (2 ml ) wasadded and the mixture was stirred for 30 min. and cooled to 0° C.Freshly prepared ZnBr₂ solution (2 ml, 1.7 mmol) in THF was introduceddropwise. After 45 min. at room temperature(2RS,6S)-2-benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran(0.5 g, 1.43 mmol) in THF (4 ml) was added and the mixture stirred for 3h. The reaction was quenched with saturated aqueous NH₄Cl solution at 0°C. THF was removed under vacuum and the residue was extracted with ethylacetate, dried (Na₂SO₄) and concentrated to give (2S,6S)-6-(4-fluorophenoxymethyl)-2-(4-tetrahydropyranoyl-1-butyne)-tetrahydropyran.The crude product was dissolved in methanol (5 ml) and 5% HCl inmethanol (10 ml) was added. The reaction mixture was stirred at roomtemperature for 2 h and neutralised with saturated aqueous Na₂CO₃solution and concentrated. The residue was extracted with ethyl acetate,dried (Na₂SO₄) and concentrated. The crude product was purified on asilica gel column to give (2S,6S)-6-(4-fluorophenoxymethyl)-2-(4-hydroxybutyn-1-yl)-tetrahydropyran(0.24 g, 70%) as a colourless liquid and as a single isomer (by HPLC).TLC:ethyl acetate-light petroleum (1:3), Rf=0.3. Optical rotation[α]_(D): −32° (c 1.1, CHCl₃). ¹H NMR (CDCl₃, 200 MHz): δ 1.6-2.0 (m,6H), 2.55 (m, 2H), 3.73 (t, J=6.35 Hz, 2H), 3.8-4.0 (m, 2H), 4.15-4.3(m,1H), 4.8 (s, 1H), 6.8-7.0 (m, 4H).

Part 7: N,O-bis-phenoxycarbonylhydroxylamine

To a solution of sodium bicarbonate (21.5 g, 0.256 mol) in water (150ml) at 0° C. was added hydroxylamine hydrochloride (8.8 g, 0.127 mol).The reaction mixture was stirred for 30 min. and phenylchloroformate (60g, 0.383 mol) was introduced directly into the vigorously stirredmixture. Sodium bicarbonate (32.3 g, 3.85 mol) in water (300 ml) wasadded to the mixture. The mixture was stirred for 30 min., the ice-bathremoved and stirring continued for an additional 2 h at roomtemperature. The resultant suspension was filtered and the filter cakewashed with water. The wet filter cake was collected, suspended inhexane, filtered and again washed with hexane. The solid was kept at 0°C. overnight to afford N,O-bis-phenoxycarbonylhydroxylamine (23.5 g,68%) as a solid. Melting point: 80-82° C. ¹H NMR (CDCl₃, 200 MHz): δ7.26(m, 5H), 7.42 (m, 5H) and 8.54 (s, 1 H).

Part 8: (2S,6S)-6-(4-Fluorophenoxymethyl)-2-(4-N,O-bis-phenoxycarbonylhydroxylamino-1-butynyl)-tetrahydropyran(Scheme XX; 16)

To an ice cooled solution of (2S,6S)-6-(4-fluorophenoxymethyl)-2-(4-hydroxybutyn-1-yl)-tetrahydropyran(0.23 g, 0.83 mmol) in dry THF (10 ml), triphenylphosphine (0.26 g, 0.99mmol) and N,O-bis-phenoxycarbonyl hydroxylamine (0.26 g, 0.95 mmol) wereadded. After 15 min., diethylazodicarboxylate (0.173 g, 0.99 mmol) wasadded dropwise. The mixture was then allowed to warn to room temperatureand stirred for 3 h. The solvent was evaporated under reduced pressureand the residue purified on a silica gel column to yield (2S,6S)-6-(4-fluorophenoxymethyl)-2-(4-N,O-bis-phenoxycarbonylhydroxylamino-1-butynyl)-tetrahydropyran(0.3 g, 70%) as a yellow colour liquid. TLC:ethyl acetate-lightpetroleum (1:3), Rf=0.6. ¹H NMR (CDCl₃, 200 MHz): δ 1.45-1.8 (m, 6H),2.75 (t, J=6.8 Hz, 2H), 3.75-3.9 (m, 2H), 4.0-4.1 (t, J=7.32 Hz, 2H),4.15-4.3 (m, 1H), 4.8 (s, 1H), 6.7-6.95 (m, 4H), 7.1-7.45 (m, 10H).

Part 9: (2S,6S)-6-(4-Fluorophenoxymethyl)-2-(4-N-hydroxyureidyl-1-butynyl)-tetrahydropyran(Scheme XX; 17)

A solution of (2S,6S)-6-(4-fluorophenoxymethyl)-2-(4-N,O-bis-phenoxycarbonylhydroxylamino-1-butynyl)-tetrahydropyran (0.3 g, 0.566 mmol) and aqueousNH₄OH in methanol (10 ml) were stirred at room temperature for 12 h.Methanol was evaporated and the residue was purified on a silica gelcolumn using light petroleum-ethyl acetate (2:3) as eluent to give (2S,6S)-6-(4-fluorophenoxymethyl)-2-(4-N-hydroxyureidyl-1-butynyl)-tetrahydropyran(0.12 g, 65%) as a yellow viscous liquid. TLC:ethyl acetate-lightpetroleum (4:1), Rf=0.3. Optical rotation [α]_(D): −28.6° (c 1.2,CHCl₃). ¹H NMR (CDCl₃, 200 MHz): δ 1.5-2.0 (m, 6H), 2.45-2.6 (t, J=6.35Hz, 2H), 3.65 (t, J=7.32 Hz, 2H), 3.75-3.9 (m, 2H), 4.1-4.3 (m, 1H),4.75.

Example 10 Preparation of (2S,6S)-6-(4-Fluorophenoxymethyl)-2-(4-N-hydroxyureidyl-1-butynyl)-tetrahydropyran(Scheme XXI; 9)

References in this Example 10 to compound numerals (generallyunderlined) designate the compounds depicted structurally in thefollowing Scheme XXI.

Reagents: a) (a), 0.55 eq. H₂O b) Mg, 1,2-dibromoethane, CuC, THF c)Pd/C, H₂, EtOH d) MX, THF, DMSO e) PhSO₂H, CaCl₂, CH₂Cl₂ f) (i)isopropyl magnesiumbromide, CH≡CCH₂CH₂OTHP, ZnBr₂, TrH (ii) 1% HCl-MeOHg) TPP, PhO₂CONHCO₂Ph, DEAD, THF h) NH₃-MeOH

Part 1: (2S)-7-Benzyloxy-1-(4-fluorophenoxy)-heptane-2-ol (Scheme XXI;3)

To a suspension of magnesium (1.4 g, 57.6 mmol) in dry THF (25 ml) wasadded 1,2-dibromoethane (1 ml) dropwise followed by addition of asolution of 1-bromo-4-benzloxy-butane (7 g, 28.8 mmol) in dry THF (25ml) slowly at room temperature. The reaction mixture was stirred for 1hour, cooled in ice-salt bath and then CuCN (50.0 mg, 0.57 mmol) wasadded followed by a solution of (S)-4-fluorophenyl-glycidyl ether (2.9g, 17.3 mmol) in dry THF (30 ml) was introduced slowly. The reaction wasstirred for 15 min and quenched with saturated aqueous ammonium chloridesolution at 0° C. THF was removed under vacuum and the residuepartitioned between EtOAc and water. The organic layer was successivelywashed with water and brine, dried over Na₂SO₄ and concentrated. Thecrude product was purified on silica gel chromatography usingEtOAc-hexane (1:6) as eluent to give(2S)-7-benzyloxy-1-(4-fluorophenoxy)-heptane-2-ol (5.8 g, 73%),[α]_(D)+12 (c 2.2, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz): δ 1.35-1.69 (m, 8H),3.45 (t, J=6.25 Hz, 2H), 3.71-3.95 (m, 2H), 4.48 (s, 2H), 6.77-7.00 (m,4H), 7.27-7.35 (m, 5H); HRMS (FAB): calcd. for C₂₀H₂₅O₃F (M+) 332.178773found 332.180309.

Part 2: (6S)-7-(4-fluorophenoxy)-heptane-1,6-diol (Scheme XXI; 4)

To a solution of (2S)-7-Benzyloxy-1-(4-fluorophenoxy)-heptane-2-ol (5.8g, 17.5 mmol) in ethanol (30 ml), 10% of Pd/C (100 mg) was added andstirred under H₂ atmosphere at normal temperature and pressure for 3hours. The reaction mixture was filtered through celite, washed withethanol and concentrated. The residue was purified by silicia gelchromatography using EtOAc-hexane (1:1) to give(6S)-7-(4-fluorophenoxy)-heptane-1,6-diol (3.92 g, 93%); [α]_(D) +12 (c3.1, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz): δ 1.29-1.69 (m, 8H), 3.65 (t, J=6.8Hz, 2H), 3.82-4.02 (m, 2H), 6.75-7.0 (m, 4H); HRMS (EI): calcd. forC₁₃H₁₉O₃F (M+) 242.131823 found 242.131900.

Part 3: (6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (Scheme XXI; 5)

To a solution of (6S)-7-(4-fluorophenoxy)-heptane-1,6-diol (3.6 g, 14.8mmol) in dry THF (60 ml) was added dropwise a solution of 2-iodobenzoicacid (5 g, 17.8 mmol) in dry DMSO (4 ml) over a period of 25 minutes atroom temperature. After 15 minutes the reaction mixture was decomposedwith crushed ice, filtered through celite and concentrated. The residuewas extracted with ethylether, washed with brine, dried over Na₂SO₄ andthe organic solvent was removed under reduced pressure. The residue waspurified by silica gel chromatography using EtOAc-hexane (1:9) to give(6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (2.2 g, 61.6%); [α]_(D)+12(c 3.8, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz): δ 1.4-1.8 (m, 6H), 2.49 (dt,2H), 3.71-4.05 (m, 4H), 6.782-7.02 (m, 4H), 9.8 (s, 1H); HRMS (FAB):calcd. for C₁₃H₁₇O₃F (M+) 240.116173 found 240.116465.

Part 4: (2RS,7S)-2-(Benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane(Scheme XXI; 6)

25% HCl was added dropwise to sodium salt of benzenesulfinic acid (5 g,30.5 mmol) until the solid dissolved. The reaction mixture was extractedwith EtOAc, dried over Na₂SO₄ and concentrated to give benzenesulfinicacid (3.9 g, 90%). To an ice-cold mixture of benzene sulfinic acid (1.8g, 12.4 mmol) and CaCl₂ (1.4 g, 12.5 mmol) in dry methylene chloride (50ml) was added dropwise a solution of(6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (2 g, 8.3 mmol) in methylenechloride (10 ml). The reaction mixture was stirred for 3 hours andfiltered through celite, and washed with methylene chloride. Thecombined organic layer was washed with saturated aqueous Na₂CO₃, water,brine and dried over Na₂SO₄. Solvent was removed under reduced pressureand the residue was purified by silica gel chromatography usingEtOAC-hexane (1:6) as eluent to give(2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.45 g,80.8%); ¹H-NMR (CDCl₃, 200 Hz): δ 1.39-2.20 (m, 7H), 2.5 (m, 1H),3.57-3.90 (m, 2H), 4.45 (m, 1H), 4.72 (dd, J=6.6, 12.0 Hz, 1H),6.57-7.00 (m, 4H), 7.36-7.96 (m, 5H).

Part 5: (2S,7S)-7-(4-Fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane(Scheme XXI; 7)

To a suspension of magnesium (0.58 g, 24.2 mmol) in dry THF (10 ml) wasadded catalytic 1,2-dibromoethane followed by dropwise addition of asolution of isopropyl bromide (1.85 g, 15.1 mmol) in THF (5 ml). Thereaction mixture was stirred for 1 hour and isoprpylmagnesiumbromide wascannulated into a 50 ml two-necked flask. A solution of4-tetrahydropyranoyl-1-butyne (1.86 g, 12.0 mmol) in THF (5 ml) wasadded and the mixture was stirred for 30 minutes followed by addition offreshly prepared ZnBr₂ solution (1 M, 7.25 ml, 7.2 mmol) in THF at 0° C.After 45 minutes(2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.2 g,6.0 mmol) in THF (10 ml) was added and the mixture stirred for 30 hours.The reaction was quenched with saturated aqueous NH₄Cl solution at 0° C.THF was removed under reduced pressure and the residue was portionedbetween EtOAc and water. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated to give(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-tetrahydropyranoyl-1-butynyl)oxepane.The crude product was dissolved in MeOH (25 ml) and 1% HCl in MeOH (5ml) was added. The hydrolysis of the THP group was completed in 2 hoursand neutralized with saturated Na₂CO₃ solution and concentrated. Thecrude product was purified by silica gel chromotography usingEtOAc-hexane (1:8) to give(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane (1.32 g,75%); [α]_(D)−74 (c 3.63, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz): δ 1.4-2.0 (m,7H), 2.12 (m, 1H), 2.3 (s, 1H), 2.46 (dt, 2H), 3.65 (t, J=3.6 Hz, 2H),3.74-3.97 (m, 2H), 4.51 (q, 1H), 6.8-7.0 (m, 4H); HRMS (EI): calcd. forC₁₇H₂₁O₃F (M+) 292.147756 found 292.147473. Also,(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane by similarprocedure: [α]_(D)+26.9 (c 2.2, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz): δ1.48-2.03 (m, 8H), 2.2 (s, 1H), 2.47 (dt, 2H), 3.69 (t, J=6.9 Hz, 2H),3.74-4.02 (m, 3H), 4.34 (dt, 2H), 6.78-7.0 (m, 4H).

Part 6:(2S,7S)-7-(4-Fluorophenoxymethyl)-2-[4-(N,O-biscarbophenoxy)-1-butynyl]oxepane(Scheme XXI; 8)

A mixture of(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane (0.9 g,3.1 mmol), TPP (1.0 g, 3.7 mmol), N,O-biscarbophenoxy-hydroxylamine (1g, 3.7 mmol) in dry THF (20 ml) was cooled to 0° C.Diethylazacarboxylate (0.64 g, 3.7 mmol) was added dropwise and thereaction mixture stirred at room temperature for 4 hours. Solvent wasremoved on rotovapor. The residue was partitioned between EtOAc andater, washed with brine, dried over Na₂SO₄ and concentrated. The productwas purified by silica gel chromatography using EtOAc-hexane (1:9) togive pure(2S,7S)-7-(4-fluorophenoxymethyl)-2-[4-(N,O-biscarbophenoxy)-1-butynyl]oxepane(1.55 g, 92%); [α]_(D)−46.0 (c 2.42, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz): δ1.39-22.0 (m, 8H), 2.73 (t, J=6.9 Hz, 2H), 3.72-4.07 (m, 4H), 4.15 (m,1H), 4.51 (dt, 1H), 6.76-7.46 (m, 4H). Also,(2R,7S)-7-(4-Fluorophenoxymethyl)-2-[4-(N,O-biscarbophenoxy)-1-butynyl]oxepaneby similar procedure: [α]_(D)+11 (c 4.3, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz):δ 1.48-2.03 (m, 8H), 3.76 (dt, 2H), 3.68-4.08 (m, 5H), 6.75-7.47 (m,14H).

Part 7:(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4N-hydroxy-ureidyl-1-butynyl)oxepane(Scheme XXI; 9)

A solution of(2S,7S)-7-(4-Fluorophenoxymethyl)-2-[4-(N,O-biscarbophenoxy)-1-butynyl]oxepane(1.4 g, 2.6 mmol) in MeOH (25 ml) was cooled to 0° C. Saturatedmethanolic ammonia solution (10 ml) was added and the reaction wasstirred for 12 hours at room temperature. Solvent was removed and theresidue was purified by silica gel chromatography using EtOAc-hexane(1:1) to give(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4N-hydroxy-ureidyl-1-butynyl)oxepane(820 mg, 92.5%); [α]_(D)−56.0 (c 2.15, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz): δ1.43-2.20 (m, 8H), 2.51 (dt, 2H), 3.7 (t, J=7.1 Hz, 2H), 3.8-3.96 (m,2H), 4.13 (m, 1H), 4.51 (q, 1H), 5.25 (s, 2H), 7.83-8.02 (m, 4H), 7.70(s, 1H); HRMS (FAB): calcd. for C₁₈H₂₄O₄N₄F (M+) 351.172011 found351.173621. 13C: 17.187, 24.589, 27.452, 32.032, 37.125, 48.887, 67.114,72.029, 72.312, 81.857, 82.414, 115.506, 115.658, 115.814, 115.965,154.903, 159.661, 161.788. Also,(2R,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane by similarprocedure: [α]_(D)+32 (c 0.5, CHCl₃), ¹H-NMR (CDCl₃, 200 Hz): δ1.42-1.94 (m, 8H), 2.44 (s, 1H), 3.57 (t, J=7.1 Hz, 2H), 3.69-3.92 (m,3H), 5.44 (s, 2H), 6.72-6.97 (m, 4H), 8.1 (s, 1H).

EXAMPLE 11 Synthesis of(2R,5R)-5-Ethynyl-2-(hydroxymethyl)-tetrahydrofuran fromL-Glyceraldehyde

References in this Example 11 to compound numerals (generallyunderlined) designate the compounds depicted structurally in Scheme XVabove.

Part 1: Ethyl (2E,4R)-4,5-isopropylidenedioxy-2-pentenoate (Scheme XV;20)

A solution of (2S,3R)-1,2-O-isopropylidene-butane-1,2,3,4-tetrol 19(11.0 g, 68.1 mmol) in CH₂Cl₂ (120 mL) containing saturated NaHCO₃solution (4.5 mL) was cooled to 0° C., treated with NaIO₄ (29.1 g, 136.3mmol) and allowed to stir at 0° C. to 20° C. After 2 to 3 h (TLCanalysis), solid Na₂SO₄ (6 g) was added and the reaction mixture wasstirred further for 15 min. The reaction mixture was filtered andsolvent evaporated (below 25° C. bath temperature) to give(S)-glyceraldehyde 19a (8.7 g) in 98% yield as a colorless liquid.Compound 19 was prepared by procedures described in J Am. Chem. Soc.,102, 6304 (1980); and J. Org. Chem., 53, 2598 (1988).

A solution of (S)-glyceraldehyde 19a (15 g, 115.4 mmol) in MeOH (200 mL)was cooled to 0°-10° C. (ice-salt bath) and treated with(carbethoxymethylene) triphenyl phosphorane (48.1 g, 138.4 mmol) inportions. After stirring at room temperature for 9 h, the solvent wasevaporated, the residue obtained on purification by columnchromatography (Si-gel, 10% EtOAc-Hexane) gave ethyl(2E,4R)-4,5-isopropylidenedioxy-2-pentenoate 20 (23 g) in 99% yield as apale yellow liquid. [α]_(D)−116.3(c 0.71, CHCl₃); ¹HNMR (CDCl₃, 200MHz): δ 1.2 (t, 3H, J 6.8 Hz, CH₃), 1.3, 1.35 (2s, 6H, CH₃), 3.5 (dd,1H, J 5.9 Hz, H-5), 4.07 (q, 2H, J 6.8 Hz, —OCH₂), 4.27 (dd, 1H, J 5.9Hz, H-5a), 5.32-5.43 (m, 1H, H-4), 5.72 (dd, 1H, J 2.2, 11.3 Hz, H-2),6.27 (dd, 1H, J 5.4, 11.3 Hz, H-3); ¹³CNMR (CDCl₃, 50 MHz): δ 13.0,25.2, 26.3, 60.1, 69.21, 73.3, 109.4, 120.5, 149.1, 165.3; EIMS m/z(relative intensity): 185 (M⁺−15, 15), 173 (6), 149 (23), 125 (20), 97(45), 43 (100); HRMS: Calculated for C₉H₁₃O₄ (M⁺−15): 145.086469;Observed: 145.087162.

Part 2: Ethyl (4R)-4,5-isopropylidenedioxy-1-pentanoate (Scheme XV; 21)

A solution of ethyl (2E,4R)-4,5-isopropylidenedioxy-2-pentenoate 20 (23g, 115 mmol) in EtOAc (50 ml) was treated with PtO₂ (0.100 g, mmol) andhydrogenated till there was no additional consumption of hydrogen (3-4h). At the end of reaction, the reaction mixture was filtered andconcentrated to afford ethyl (4R)-4,5-isopropylidenedioxy-1-pentanoate21 (23 g) in 99% yield as a colorless liquid. [α]_(D)−4.0(c 2.0, CHCl₃);¹HNMR (CDCl₃, 200 MHz): δ 1.25 (t, 3H, J 6.8 Hz, CH₃), 1.29, 1.32 (2s,6H, CH₃), 1.75-1.89 (m, 2H, H-3), 2.3-2.45 (m, 2H, H-2), 3.5 (t, 1H, J6.5 Hz, H-5), 3.92-4.15 (m, 4H, H-4,5a, —OCH₂); ¹³CNMR (CDCl₃, 50 MHz):δ 14.0, 25.4, 26.8, 28.6, 30.2, 60.1, 68.8, 74.7, 108.7, 172.6. EIMS m/z(relative intensity): 203 (M⁺+1, 23), 173 (16.4), 143 (13.4), 101 (100),43 (97); HRMS: Calculated for C₈H₁₃O₄ (M⁺−29): 173.081384; Observed:1173.081619.

Part 3: (2R)-1,2-Isopropylidenedioxy-5-pentanol (Scheme XV; 22)

A suspension of LAH (4.93 g, 130.4 mmol) in THF (50 mL) was cooled to 0°C. and treated drop wise with a solution of ethyl(4R)-4,5-isopropylidenedioxy-1-pentanoate 21 (22 g, 108.9 mmol) in THF(75 mL). The reaction mixture was warmed to room temperature, thenallowed to stir for 3 h and treated with a saturated solution of Na₂SO₄(15 mL). After stirring for additional 30 min., it was filtered throughcelite and washed with EtOAc (3×75 mL). The combined organic layers werewashed with NaCl solution and evaporated to provide the(2R)-1,2-isopropylidenedioxy-5-pentanol 22 (17 g) in 97% yield as acolorless liquid. [α]_(D)−10.3(c 0.75, CHCl₃); ¹HNMR (CDCl₃, 200 MHz): δ1.35, 1.4 (2s, 6H), 1.6-1.75 (m, 4H, H-3,4), 1.92 (br.s, 1H, OH), 3.5(t, 1H, J 6.1 Hz, H-1), 3.6-3.72 (m, 2H, H-5), 3.98-4.16 (m, 2H,H-1a,2); ¹³CNMR (CDCl₃, 50 MHz): δ 25.6, 26.8, 29.0, 30.1, 62.4, 69.4,75.9, 108.8; EIMS m/z (relative intensity): 145 (M⁺−15, 13.4), 85 (32),72 (18), 57 (13.4), 43 (100); HRMS: Calculated for C₇H₁₃O₃ (M⁺−15):145.086468; Observed: 145.087162.

Part 4: (4R)-4,5-Isopropylidenedioxy-1-pentanal (Scheme XV; 23)

Method A: A stirred solution of (2R)-1,2-isopropylidenedioxy-5-pentanol22 (17 g, 106.3 mmol) in CH₂Cl₂ (200 mL) was treated with PDC (59.9 g,159.3 mmol) in portions and allowed stir at 40° C. for 5 h. The reactionmixture was diluted with ether (4×300 mL) and decanted through a smallpad of silica gel. Evaporation of solvent afforded(4R)-4,5-isopropylidenedioxy-1-pentanal 23 (15 g) in 89% yield as a paleyellow liquid.

Method B: A stirred solution of (2R)-1,2-isopropylidenedioxy-5-pentanol22 (0.800 g, 5.0 mmol) in DMSO (5 mL) was cooled to 0° C., treated withIBX (1.47 g, 5.26 mmol) in portions while maintaining the temperaturebelow 0° C. and stirred at room temperature for 4 h. The reactionmixture was treated with saturated NaHCO₃ solution, filtered throughcelite and washed with EtOAc (3×30 mL). Two layers were separated andorganic layer was washed with water, brine and dried (Na₂SO₄).Evaporation of solvent gave (4R)-4,5-isopropylidenedioxy-1-pentanal 23(16.2 g) in 78% yield as a yellow liquid. [α]_(D)+0.3(c 2.0, CHCl₃).

Part 5: Ethyl (2E,6R)-6,7-isopropylidenedioxy hept-2-enoate (Scheme XV;24)

A solution of (4R)-4,5-isopropylidenedioxy-1-pentanal 23 (15 g, 94.9mmol) in benzene (200 mL) was treated with (carbethoxymethylene)triphenyl phosphorane (39.6 g, 113.8 mmol) and heated at reflux for 6 h.Solvent was evaporated and the residue purified by column chromatography(Si-gel, 10% EtOAc-hexane) to afford ethyl(2E,6R)-6,7-isopropylidenedioxy hept-2-enoate 24 (14 g) in 65% yield asa pale yellow liquid. [α]_(D)−5.4(c 1.2, CHCl₃); ¹HNMR (CDCl₃, 200 MHz):δ 1.3 (t, 3H, J 6.8 Hz,CH₃), 1.34, 1.4 (2s, 6H), 1.61-1.7 (m, 2H, H-6),2.2-2.42 (m, 2H, H-4), 3.5 (t, 1H, J 6.8 Hz, H-7a), 3.99-4.26 (m, 4H,H-6,7, —OCH₂), 5.82 (td, 1H, J 2.25, 15.75 Hz, H-2), 6.94 (dt, 1H, J6.8, 15.75 Hz, H-3); ¹³CNMR (CDCl₃, 50 MHz): δ 14.0, 25.4, 26.7, 28.2,31.9, 60.0, 69.0, 74.9, 108.7, 121.7, 147.7, 166.3; EIMS m/z(relativeintensity): 213 (M⁺−15, 9), 95 (40.2), 67 (25.3), 55 (53.7), 41 (100);HRMS: Calculated for C₁₁H₁₇O₄ (M⁺−15): 213.112684; observed: 213.112732.

Part 6: (2E,6R)-6,7-Isopropylidenedioxy hept-2-ene-1-ol (Scheme XV; 25)

A stirred solution of ethyl (2E,6R)-6,7-isopropylidenedioxyhept-2-enoate 24 (13.87 g, 60.8 mmol) in dry CH₂Cl₂ (60 mL) was cooledto −20° C. (CCl₄+dry ice bath) and treated with a solution of DIBAL-H(17.27 g, 121.6 g, mmol; 2.5M solution in hexane) drop wise. Afterstirring for 2 h, the reaction mixture was warmed to 0° C., treated dropwise with MeOH (10 mL) to obtain a gelatin cake. The mixture was dilutedwith CH₂Cl₂ (100 mL) and stirred for 15 min. A solution of Na-Ktartarate (90 mL) was added drop wise and stirred for an additional 45min. Reaction mixture was filtered through celite and washed with CH₂Cl₂(2×50 mL). The organic layer was washed with water (2×100 mL), brine (50mL), dried (Na₂SO₄) and evaporated to give(2E,6R)-6,7-isopropylidenedioxy hept-2-ene-1-ol 25 (11 g) in 98.2% yieldas a colorless liquid. [α]_(D)−13.2 (c 2.5, CHCl₃); ¹HNMR (CDCl₃, 200MHz): δ 1.16,1.2 (2s, 6H, CH₃), 1.46-1.74 (m, 2H, H-5), 1.79-198 (m, 1H,—OH), 2.02-2.19 (m, 2H, H-4), 3.36-3.78(m, 3H, H-6,7), 4.02-4.12 (m, 2H,H-1), 5.61-5.71 (m, 2H, H-2,3); ¹³CNMR (CDCl₃, 50 MHz): δ 25.3, 26.5,28.0, 32.7, 62.8, 68.9, 75.1, 108.3, 129.8 (2C); EIMS m/z (relativeintensity): 171 (M⁺−15, 35.8), 93 (22.3), 67 (37.3), 55 (26.8), 43(100); HRMS: Calculated for C9H15O3 (M+−15): 171.102120; observed:171.102195.

Part 7: (2R,3R,6R)-2,3-Epoxy-6,7-isopropylidenedioxy heptan-1-ol (SchemeXV; 26)

To a stirred and cooled (−20° C.) suspension of molecular sieves (4 A,1.25 g) in CH₂Cl₂ (10 mL) under N₂ atmosphere, (−)-diisopropylD-tartarate (7.6 g, 32.4 mmol), titanium(IV) isopropoxide (7.68 g, 27.02mmol) and cumene hydroperoxide (8.22 g, 54 mmol) were addedsequentially. After 20 min., the resulting mixture was treated drop wiseaddition of a solution of (2E,6R)-6,7-isopropylidenedioxyhept-2-ene-1-ol 25 (5 g, 26.88 mmol) in CH₂Cl₂ (15 mL) and stirred foradditional 3h. The reaction mixture was quenched with 10% NaOH solutionsaturated with NaCl (15 mL) and filtered through celite. Evaporation ofsolvent and purification of residue by column chromatography (Si-gel,1:1 EtOAc-hexane) gave (2R,3R,6R)-2,3-epoxy-6,7-isopropylidenedioxyheptan-1-ol 26 (4.15 g) in 76.4% yield as a colorless liquid.[α]_(D)+24.3(c 0.3, CHCl₃); ¹HNMR (CDCl₃, 200 MHz): δ 1.32, 1.38 (2s,6H, CH₃), 1.58-1.78 (m, 4H, H-4,5), 2.84-3.01 (m, 2H, H-2,3), 3.5 (t,1H, J 6.1 Hz, H-7), 3.6 (dd, 1H, J4.7, 11.75 Hz, H-1), 3.85 (dd, 1H, J3.29, 11.75, H-1a), 3.98-4.2 (m, 2H, H-6,7′); ¹³CNMR (CDCl₃, 50 MHz): δ25.5, 26.8, 27.6, 29.6, 55.3, 58.3, 61.6, 69.1, 75.1, 108.8; EIMS M/Z(relative intensity): 188 (M⁺−15, 14.9), 144 (85), 101 (47.7), 83 (95),43 (100); HRMS: Calculated for C₉H₁₅O₄ (M−15): 187.097034; Observed:187.096634.

Part 8: (2R,3R,6R)-1-Chloro-2,3-epoxy-6,7-isopropylidenedioxy heptane(Scheme XV; 27)

A stirred mixture of (2R,3R,6R)-2,3-epoxy-6,7-isopropylidenedioxyheptan-1-ol 26 (3.8 g, 18.8 mmol), Ph₃P (7.4 g, 28.3 mmol) and NaHCO₃(0.6 g) in CCl₄ (50 mL) was heated at reflux for 3 h. The solvent wasevaporated and residue obtained purified by column chromatography (Si-gel, 20% EtOAc-hexane) to give(2R,3R,6R)-1-chloro-2,3-epoxy-6,7-isopropylidenedioxy heptane 27 (2.8 g)in 67.8% yield as a colorless liquid. [α]_(D)+8.16(c 0.7, CHCl₃); ¹HNMR(CDCl₃, 200 MHz): δ 1.31, 1.36 (2s, 6H, CH₃), 1.72 (m, 4H, H-4,5),2.8-2.9 (m, 1H, H-2), 2.91-3.02 (m, 1H, H-3), 3.32-3.68 (m, 3H, H-1,7),3,95-4.19 (m, 2H, H-6,7a); ¹³CNMR (CDCl₃, 50 MHz): δ 25.6, 26.9, 27.6,29.6, 44.5, 57.0, 58.3, 69.2, 75.1, 108.9; EIMS m/z (relativeintensity): 205 (M⁺−15, 35.8), 145 (23), 83 (61), 72 (98), 43 (100);HRMS: Calculated for C₉H₁₄ClO₃ (M⁺−15): 205.063147; Observed:205.062719.

Part 9: (3R,6R)-3-Hydroxy-6,7-isopropylidenedioxy-hept-1-yne (Scheme XV;28):

To freshly prepared LDA [prepared from diisopropyl amine (4.6 g, 45.45mmol) and n-BuLi (2.91 g, 45.54 mmol; 1.4N hexane solution)] in THF (10mL), a solution of (2R,3R,6R)-1-chloro-2,3-epoxy-6,7-isopropylidenedioxyheptane 27 (2.5 g, 11.36 mmol) in THF (20 mL) was added at −40° C.(CH₃CN+dry ice bath). After 3 h, the reaction was quenched with aq.NH₄Cl solution and diluted with CH₂Cl₂ (50 mL). The organic layer wasseparated, washed with water (3×20 mL), brine (200 mL) and dried(Na₂SO₄), evaporated and residue purified by column chromatography(Si-gel, 15% EtOAc-hexane) to furnish(3R,6R)-3-hydroxy-6,7-isopropylidenedioxy-hept-1-yne 28 (2.0 g) in 95.2%yield as a pale yellow liquid. [α]_(D)−3.02(c 2.2, CHCl₃); ¹HNMR (CDCl₃,200 MHz): δ 1.32, 1.39 (2s, 6H, CH₃), 1.64-1.94 (m, 4H, H-4,5),2.19-2.21 (br.s, 1H, OH), 2.39 (d, 1H, J 2.3 Hz, H-1), 3.5 (t, 1H, J 5.7Hz, H-7), 3.96-4.16 (m, 2H, H-6,7a), 4.34-4.45 (m, 1H, H-3); ¹³CNMR(CDCl₃, 50 MHz): δ 25.4, 26.6, 28.8, 33.5, 61.3, 69.0, 72.7, 75.3, 84.7,108.7; EIMS m/z (relative intensity): 169 (M⁺−15, 22.3), 109 (20.8), 81(37.3), 55 (35.8) 43 (100); HRMS: Calculated for C₉H₁₃O₃ (M−15):169.086469; Observed: 169.086140.

Part 10: (3R,6R)-3-Acetoxy-6,7-isopropylidenedioxy-hept-1-yne (SchemeXV; 29)

A solution of hydroxy-6,7-isopropylidenedioxy-hept-1-yne 28 (1.8 g, 9.8mmol) and pyridine (3.1 g, 39.2 mmol) in CH₂Cl₂ (15 mL) containing DMAP(catalytic) at 0° C. was treated with Ac₂O (1.2 g, 11.7 mmol) andstirred at room temperature for 30 min. After completion, the reactionwas diluted with CH₂Cl₂ (50 mL), sequentially washed with CuSO₄ solution(3×20 mL), saturated aq. NaHCO₃ solution (20 mL), water (20 mL), brine(20 mL) and dried. Evaporation of solvent and purification of residue bycolumn chromatography (Si-gel, 10% EtOAc-hexane) gave(3R,6R)-3-acetoxy-6,7-isopropylidenedioxy-hept-1-yne 29 (2.15 g) in97.2% yield as a yellow liquid. [α]_(D)+37.5(c 2.1, CHCl₃); ¹HNMR(CDCl₃, 200 MHz): δ 1.3, 1.39 (2s, 6H, CH₃), 1.64-2.0 (m, 2H, H-4,5),2.06 (s, 3H, CH₃), 2.4 (d, 1H, J 2.0 Hz, H-1), 3.5 (t, 1H, J 5.7 Hz,H-7), 3.95-4.13 (m, 2H, H-6,7a), 5.31-5.41 (m, 1H, H-3); ¹³CNMR (CDCl₃,50 MHz): δ 20.8, 25.5, 26.8, 28.8, 30.7, 63.3, 69.1, 73.7, 75.1, 80.7,108.9, 169.6; EIMS m/z (relative intensity): 211 (M⁺−15, 29.8), 169(11.9), 91 (22.3), 72 (23), 43 (100); HRMS: Calculated for C₁₁H₁₅O₄(M⁺−15): 211.097034; Observed; 211.095947.

Part 11: (3R,6R)-3-Acetoxy-6,7-dihydroxy-hept-1-yne (Scheme XV; 30)

A solution of (3R,6R)-3-acetoxy-6,7-isopropylidenedioxy-hept-1-yne 29 (2g, 8.8 mmol) in MeOH (150 mL) containing catalytic amount of PTSA wasstirred at 0° C. for 8 h. The reaction mixture was neutralized withsaturated sat. NaHCO₃ solution, evaporated to remove MeOH and extractedwith EtOAc (3×50 mL). Organic layer were evaporated and the residuefiltered through a small pad of silica gel with 1:1 EtOAc-hexane toafford (3R,6R)-3-acetoxy-6,7-dihydroxy-hept-1-yne 30 (1.2 g) in 72.9%yield as a colorless syrup. [α]_(D)+83.2 (c 1.2, CHCl₃); ¹HNMR (CDCl₃,200 MHz): δ 1.5-1.7 (m, 2H, H-4), 1.75-2.05 (m, 2H, H-5), 2.14 (s, 3H,—OAc), 2.45 (d, 2H, H-1), 2.57 (br.s, 1H, OH), 3.35-3.5 (m, H, H-7),3.57-3.8 (m, 2H, H-6,7a), 5.32-5.47 (m, 1H, H-3); CIMS m/z (relativeintensity): 187 (M+1, 74.6), 127 (59.7), 109 (35.8), 81 (56.7), 43(100); HRMS Calculated for C₉H₁₅O₄ (M+1): 187.097034; Observed:187.096547.

Part 12: (3R,6R)-3-Acetoxy-6-hydroxy-7-p-toluene sulfonyloxy-hept-1-yne(Scheme XV; 31)

A solution of (3R,6R)-3-acetoxy-6,7-dihydroxy-hept-1-yne 30 (1.1 g, 5.9mmol) in CH₂Cl₂ (20 mL) containing pyridine (0.934 g, 11.82 mmol) wascooled to 0° C., treated with p-TsCl (1.12 g, 5.91 mmol) and stirred atroom temperature for 8 h. The reaction mixture was diluted with CH₂Cl₂and washed sequentially with water (20 mL), CuSO₄ solution (3×20 mL) andwater (20 mL). Organic layer was dried (Na₂SO₄), evaporated and residueobtained was purified by column chromatography (Si-gel, 10%EtOAc-Hexane); first eluted was (3R,6R)-3-acetoxy-6,7-di-p-toluenesulfonyloxy-hept-1-yne 31a (0.23 g) in 8% yield as a yellow syrup. ¹HNMR(CDCl₃, 200 MHz): δ 1.5-1.85 (m, 4H, H-3,4), 2.05 (s, 3H, OAc),2.41-2.52 (m, 7H, H-7, Ar—CH₃), 4.0 (d, 2H, J4.8 Hz, H-1), 4.58-4.62 (m,1H, H-2), 5.12-5.26 (m,1H, H-5), 7.28-7.44, 7.64-7.81 (m, 4H each,Ar—H).

Second eluted was (3R,6R)-3-acetoxy-6-hydroxy-7-p-toluenesulfonyloxy-hept-1-yne 31 (1.1 g) in 55% yield as a yellow syrup.[α]_(D)+28.1 (c 1.0, CHCl₃); ¹HNMR (CDCl₃, 200 MHz): δ 1.35-1.68 (m, 3H,H-4, —OH), 1.68-2.0 (m, 2H, H-5), 2.08 (s, 3H, CH₃), 2.4 (d, 1H, J 2.4Hz, H-1), 2.46 (s, 3H, Ar—CH₃), 3.79-4.06 (m, 3H, H-6,7), 5.35 (td,1H, J4.8, 7.2 Hz, H-3), 7.36 (d, 2H, J 7.2 Hz, Ar—H), 7.8 (d, 2H, J 7.2 Hz,Ar—H). FABMS m/z (relative intensity): 341(M+1, 13.8), 281(50),155(54.1), 133(52.7), 109(100). HRMS: Calculated for C₁₆H₂₁O₆S(M+1):341.105885; Observed:341.104916.

Part 13: (2R,5R)-5-Ethynyl-2-(hydroxymethyl)-tetrahydrofuran (Scheme XV;32)

To a solution of (3R,6R)-3-acetoxy-6-hydroxy-7-p-toluenesulfonyloxy-hept-1-yne 31 (0.6 g, 1.76 mmol) in MeOH (10 mL) at roomtemperature, K₂CO₃ (0.536 g, 3.88 mmol) was added and the mixture wasstirred for 2 h. It was treated with NH₄Cl solution, evaporated MeOH andthe residue extracted with EtOAc (3×20 mL). Organic layer was washedwith water (10 mL), brine (10 mL), dried (Na₂SO₄) evaporated. Theresidue obtained was purified by column chromatography (Si-gel, 20%EtOAc-hexane) to furnish(2R,5R)-5-ethynyl-2-(hydroxymethyl)-tetrahydrofuran 32 (0.22 g) in 99%yield as a colorless liquid. [α]_(D)+20.0 (c 1.0, CHCl₃); ¹HNMR (CDCl₃,200 MHz): δ 1.89-2.38 (m, 4H, H-3,4), 2.4 (br.s, 1H, OH), 2.46 (d, 1H, J2.2 Hz, H-7), 3.55 (dd, 1H, J 4.5, 11.25 Hz, H-1), 3.72 (dd, 1H, J 4.0,11.25 Hz, H-1a), 4.0-4.15 (m, 1H, H-2), 4.52-4.66 (m,1H, H-5); ¹³CNMR(CDCl₃, 50 MHz): δ 26.6, 29.6, 33.6, 64.6, 68.3, 73.0, 80.7; EIMS m/z(relative intensity): 125 (M⁺−1, 8), 95 (74.6), 67 (100), 53 (40), 41(80); HRMS: Calculated for C₇H₉O₂ (M−1): 125.060255; Observed:125.060322.

Part 14: (2R,5R)-5-Ethynyl-2-(p-toluenesulfonyloxymethyl)-tetrahydrofuran (Scheme XV; 33)

A solution of alcohol(2R,5R)-5-ethynyl-2-(hydroxymethyl)-tetrahydrofuran 32 (0.22 g, 1.75mmol) in pyridine (0.6 mL) was treated with p-TsCl (0.354 g, 1.86 mmol)and the mixture stirred at room temperature for 3 h. The reactionmixture was diluted with CH₂Cl₂ (20 mL) and washed sequentially withwater (10 ML), CuSO₄ solution (2×10 mL), brine (10 mL) and dried(Na₂SO₄). Evaporation of solvent and purification of residue by columnchromatography (Si-gel, 15% EtOAc-hexane) gave(2R,5R)-5-ethynyl-2-(p-toluene sulfonyloxymethyl)-tetrahydrofuran 33(0.33 g) in 63.9% yield as a yellow syrup. [α]_(D)+10.0 (c 0.54, CHCl₃);¹HNMR (CDCl₃, 200 MHz): δ 1.84-2.11 (m, 4H, H-3,4) 2.32 (d, 1H, J 2.1Hz, H-7), 2.45 (s, 3H, CH₃), 3.92-4.2 (m, 3H, H-2,1,1a), 4.48-4.58 (m,1H, H-5), 7.34 (d, 2H, J 7.6 Hz, Ar—H), 7.8 (d, 2H, J 7.6 Hz, Ar—H);CIMS m/z (relative intensity): 281(M+1, 100), 109(49.2), 117(31.3),81(7.0), 43(100); HRMS: Calculated for C₁₄H₁₇O₄S (M+1):281.084756;Observed: 281.083610.

Part 15: (2R,5R)-5-Ethynyl-2-(4-fluoro phenoxymethyl)-tetrahydrofuran(Scheme XV; 34)

To a stirred suspension of NaH (0.032 g, 1.33 mmol) in DMF (3 mL), asolution of (2R,5R)-5-ethynyl-2-(p-toluene sulfonyloxymethyl)-tetrahydrofuran 33 (0.33 g, 1.1 mmol) in DMF (3 mL) was addedand heated at 80° C. for 5 h. The reaction mixture was cooled to roomtemperature and treated with NH₄Cl solution. It was extracted with ether(2×10 mL) and the organic layer was washed with water (2×10 mL), brine(10 mL) and dried (Na₂SO₄). Evaporation of solvent and purification ofresidue by column chromatography (Si-gel, 7% EtOAc-hexane) afforded(2R,5R)-5-ethynyl-2-(4-fluoro phenoxy methyl)-tetrahydrofuran 34 (0.21g) in 85.7% yield as a colorless liquid, whose spectral data isaccordance with the reported reference values. [α]_(D)+16.0 (c 1.0,CHCl₃); ¹HNMR (CDCl₃, 200 MHz): δ 1.88-2.32 (m, 4H, H-3,4), 2.41 (d, 1H,J 2.3 Hz, H-7), 3.9 (dd, 1H, J 4.6, 9.1 Hz, H-1), 4.06 (dd, 1H, J 5.9,9.1 Hz, H-1a), 4.22-4.36 (m, 1H, H-2), 4.58-4.69 (m, 1H, H-5), 6.75-7.02(m, 4H, Ar—H); ¹³CNMR (CDCl₃, 50 MHz): δ 28.2, 33.1, 68.5, 71.2, 72.9,76.3, 83.7, 115.4, 115.6, 115.8, 115.9, 154.9, 159.6; EIMS m/z (relativeintensity): 220 (M⁺, 10.4), 125 (14.9), 95 (94), 67 (100), 41 (59.7);HRMS: Calculated for C₁₃H₁₃O₂F (M⁺): 220.089958; Observed: 220.089497.

EXAMPLE 12 Keto-epoxide Cyclisation

References in this Example 12 to compound numerals (generallyunderlined) designate the compounds depicted structurally in Scheme XVIabove.

Part 1: Non-8-ene-1-p-methoxy phenyl methyl-5-oxo-3-yn-1-ol (Scheme XVI;54)

A. Mixed anhydride (Scheme XVI; 53): A stirred and cooled (−10° C. to 0°C.) solution of pent-4-enoic acid (0.5 g, 5 mmol) and freshly distilledEt₃N (0.505 g, 5 mmol) in dry ether (5 mL), was treated with ethylchloro formate (0.542 g, 5 mmol). The reaction mixture was allowed toreach room temperature and stirred for 3 h. The reaction mixture wasfiltered and washed with ether. Organic layer was washed with saturatedNaHCO₃ solution (25 mL), water (25 mL), brine (20 mL) and dried(Na₂SO₄). Evaporation of solvent under vacuum at room temperatureafforded mixed anhydride 53 (0.79 g) in 91.8% yield as a colorlesssyrup.

B. Non-8-ene-1-p-methoxy phenyl methyl-5-oxo-3-yn-1-ol (Scheme XVI; 54):A stirred solution of 1-p-methoxy phenyl methyl-but-3-yn-1-ol (52: 1.12g, 5.91 mmol) in dry THF (5 mL) was cooled to −78° C. and treated withn-BuLi (4 mL, 5.91 mmol; 1.5 N hexane solution) dropwise. After 30 min.,a solution of anhydride 53 (0.78 g, 4.54 mmol) in THF (5 mL) was addedand stirred at the same temperature for 2hours. The reaction mixture wasquenched with aq. NH₄Cl solution (10 mL) and extracted with EtOAc (2×25mL). Organic layer was washed with brine (25 mL), dried (Na₂SO₄),evaporated and purified the residue by column chromatography (Si-gel,8:1 Hexane-EtOAc) to afford non-8-ene-1-p-methoxy phenylmethyl-5-oxo-3-yn-1-ol (54; 0.35 g) in 27% yield as a colorless syrup.¹HNMR (CDCl₃, 200 MHz): δ 2.32-2.46 (m, 2H, H-7), 2.56-2.69 (m, 4H,H-6,2), 3.59 (t, 2H, J 8.37 Hz, H-1), 3.8 (s, 3H, —OMe), 4.47 (s, 2H,—OCH₂), 4.95-5.11 (m, 2H, H-9), 5.67-5.9 (m, 1H, H-8), 6.84, 7.22 (2d,2H each, J 9.3 Hz, Ar—H).

Part 2: 1,2-Epoxy-9-p-methoxy phenyl methyl-5-oxo-non-6-yn-9-ol (SchemeXVI; 55)

A solution of non-8-ene-1-p-methoxy phenyl methyl-5-oko-3-yn-1-ol 54(0.2 g, 0.73 mmol) in acetone (5 mL) was sequentially treated with solidNaHCO₃ (0.306 g, 3.65 mmol), water (5 mL) followed by a solution ofoxone (0.448 g, 073 mmol) in aqueous. 4×10⁻⁴ M EDTA disodium solution(10 mL) dropwise at 0° C. and stirred at room temperature for 4 h. Thereaction mixture was filtered and washed with EtOAc (10 mL). The aqueouslayer was extracted with EtOAc (2×10 mL) and combined organic layerswere washed with brine (20 mL) and dried (Na₂SO₄). Evaporation ofsolvent and purification of residue by column chromatography (Si-gel,15% EtOAc in hexane) gave 1,2-epoxy-9-p-methoxy phenylmethyl-5-oxo-non-6-yn-9-ol 55 (0.1 g) in 48% yield as a colorless syrup.¹HNMR (CDCl₃, 200 MHz): δ 1.62-1.82 (m, 1H, H-3), 1.9-2.1 (m, 1H, H-3′),2.41-2.57 (m, 1H, H-1), 2.57-2.74 (m, 5H, H-1′, 4,8), 2.85-2.96 (m, 1H,H-2), 3.58 (t, 2H, J 8.13 Hz, H-9), 3.8 (s, 3H, —OMe), 4.45 (s, 2H,—OCH₂), 6.84, 7.22 (2d, 2H each J 9.3 Hz, Ar—H).

Part 3:(2S,5RS)-2-(Hydroxymethyl)-5-(1-p-methoxyphenylmethylenoxy-but-3-yn-4-yl)-tetrahydrofuran(Scheme XVI; 56)

To a stirred and cooled −78° C. solution of 1,2-epoxy-9-p-methoxy phenylmethyl-5-oxo-non-6-yn-9-ol 55 (0.075 g. 0.26 mmol) in CH₂Cl₂ (52 mL;0.005M solution), a solution of BH₃-DMS (0.25 mL, 0.26 mmol; 1 Msolution in CH₂Cl₂) was added dropwise. After 3 hours, the reactionmixture was quenched with aq. NH₄Cl solution (10 mL) at 0° C. andextracted with EtOAc (2×10 mL). Organic layer was washed with water(2×10 mL), brine (10 mL) and dried (Na₂SO₄). Evaporation of solvent andpurification of residue by column chromatography (Si-gel, 25% EtOAc inhexane) gave racemic2-(Hydroxymethyl)-5-(1-p-methoxyphenylmethylenoxy-but-3-yn-4-yl)-tetrahydrofuran56 (0.025 g) in 34% yield as a colorless syrup. The compound 56 thusobtained by this approach is comparable to compound 39 (Scheme IX) byTLC analysis as well as ¹HNMR data.

EXAMPLE 13 Di-hydroxy Compound

References in this Example 13 to compound numerals (generallyunderlined) designate the compounds depicted structurally in Scheme XVIIabove.

Mannose diacetonide 70 is converted to the corresponding sulfide 72 onreaction with diphenyl sulfide and tributyl phosphone indichloromethane. The 5,6-acetonide group of the reaction product ishydrolyzed with 60% aqueous acetic acid to afford the diol, which oncleavage with sodium periodate gives the aldehyde. Reaction of thealdehyde with sodium borohydride gives the alcohol 73, which on reactionwith tosyl chloride gives the tosylate. Reaction of the tosylate withthe sodium salt of p-fluorophenol in dimethyl formamide gives the arylether 74. The sulfide is oxidized with oxone to sulfone. The resultingsulfone on further reaction with magneium acetylide of4-OPM-but-1-yn-4-ol (prepared from ethyl magnesium bromide andhomoproargyl alcohol MPM ether) in the presence of zinc bromide givesthe acetylene 75. The acetylene compound is reacted with DDQ to give thealcohol, which in turn on reaction with N-hydroxy urea derivative andfurther reaction with ammonia provides compound 76.

EXAMPLE 14 Human Whole Blood Assay

The following compound of the invention was tested for Leukotriene B₄inhibition in the human whole blood assay detailed below.

Heparinized human whole blood was pre-incubated with selectedconcentrations of the test compound for 15 minutes at 37° C. andstimulated with 50 μM calcium ionphor for 30 minutes at 37° C. Thereaction was stopped by placing samples on ice and cold centrifugationat 4° C. for 10 minutes at 1100×g. Test sample plasma was diluted inbuffer and assayed for LTB₄ content. Test compound activity wasdetermined as per Cayman LTD EIA and evaluated as IC₅₀ [nM]. Thecompound had an IC₅₀ of 148 nM. Other tested stereoisomers of the abovecompound exhibited differing IC₅₀ values.

The invention has been described in detail including preferredembodiments thereof. However, it will be understood that those skilledin the art, upon consideration of this disclosure, may makemodifications and improvements thereon without departing from the spiritand scope of the invention as set forth in the following claims.

What is claimed is:
 1. A method for preparing a hydroxy-substitutedtetrahydrofuran, comprising: a) reacting an arylhydroxy compound and anepoxy compound to form an epoxy-aryl ether; b) reacting the epoxy-arylether with an active methylene compound to form a lactone; and c)reducing the lactone to provide a hydroxy-substituted tetrahydrofuran.2. The method of claim 1 wherein the arylhydroxy compound is ahydroxy-substituted carbocyclic aryl compound.
 3. The method of claim 1wherein the arylhydroxy compound is a hydroxy-substituted heteroarylcompound.
 4. The method of claim 1 wherein the epoxy compound is aglycidyl compound substituted with an electron-withdrawing group.
 5. Themethod of claim 1 wherein the epoxy compound is an epihalohydrin or aglycidyl sulfonyl ester compound.
 6. The method of claim 1 wherein theepoxy compound is optically active.
 7. The method of claim 1 wherein theepoxy compound is racemic.
 8. The method of claim 1 or 7 wherein thearyihydroxy compound and the epoxide are reacted in the presence of anoptically active compound.
 9. The method of claim 1 wherein the epoxideis racemic and the arylhydroxide and epoxide are reacted in the presenceof an optically active compound to form an optically active epoxy-arylether.
 10. The method of claim 1 wherein the active methylene compoundis a diester or a half-ester thereof.
 11. The method of claim 1 whereinthe active methylene compound is a dialkyl malonate.
 12. The method ofclaim 1 further comprising activating the hydroxy group of thehydroxy-substituted tetrahydrofuran and substituting the activatedtetrahydrofuran position.
 13. The method of claim 12 wherein thetetrahydrofuran position is substituted with a nucleophilic compound.14. The method of claim 12 wherein the tetrahydrofuran position issubstituted with a 1-alkynyl compound.
 15. The method of any one ofclaims 12-14 wherein the substitution produces an enantiomeric excess ofa stereoisomer.
 16. The method of claim 15 wherein the substitutionproduces a steroisomer that is present in at least about 60 percentrelative to the other steroisomer.
 17. The method of claim 15 whereinthe substitution produces a steroisomer that is present in at leastabout 70 percent relative to the other steroisomer.
 18. The method ofclaim 15 wherein the substitution produces a trans steoroisomer that ispresent in at least about 60 percent relative to the cis steroisomer.19. The method of claim 15 wherein the substitution produces a transsteoroisomer that is present in at least about 70 percent relative tothe cis steroisomer.
 20. The method of claim 15 wherein the substitutionproduces a cis steoroisomer that is present in at least about 60 percentrelative to the trans steroisomer.
 21. The method of claim 15 whereinthe substitution produces a cis steoroisomer that is present in at leastabout 70 percent relative to the trans steroisomer.
 22. The method ofclaim of claim 1 wherein the hydroxy-substituted tetrahydrofuran isrepresented by the following formula:

wherein Ar is optionally substituted carbocyclic aryl or optionallysubstituted heteroaryl.
 23. The method of claim 22 wherein Ar isoptionally substituted carbocyclic aryl.
 24. The method of claim 22wherein Ar is optionally substituted phenyl.
 25. A method for preparinga substituted γ-butyrolactone, comprising: a) reacting mannitol with analkanoyl compound to form a trialkylene mannitol; b) hydrolyzing thetrialkylene mannitol to provide a 2,5-O-alkylene-mannitol; and c)functionalizing secondary hydroxy groups of the 2,5-O-alkylene-mannitolto provide a fused ring cyclic ether comprising a first cyclic etherfused to a second cyclic ether; d) reacting the fused ring cyclic etherwith an optionally substituted arylhydroxy or arylalkyhdroxy compound toform a bis-arylether or bis-arylalkylether and e) cleaving thebis-arylether or bis-arylalkylether to form a substitutedγ-butyrolactone.
 26. A method for preparing a lactone, comprising: a)reacting an arylhydroxy compound and an epoxy compound to form anepoxy-aryl ether; and b) reacting the epoxy-aryl ether with an activemethylene compound to form a lactone.
 27. The method of claim 26 whereinthe arylhydroxy compound is a hydroxy-substituted carbocyclic arylcompound.
 28. The method of claim 26 wherein the arylhydroxy compound isa hydroxy-substituted heteroaryl compound.
 29. The method of claim 26wherein the epoxy compound is a glycidyl compound substituted with anelectron-withdrawing group.
 30. The method of claim 26 wherein the epoxycompound is an epihalohydrin or a glycidyl sulfonyl ester compound. 31.The method of claim 26 wherein the epoxy compound is optically active.32. The method of claim 26 wherein the, epoxy compound is racemic. 33.The method of claim 26 or 32 wherein the arylhydroxy compound and theepoxide are reacted in the presence of an optically active compound. 34.The method of claim 26 wherein the epoxide is racemic and thearylhydroxide and epoxide are reacted in the presence of an opticallyactive compound to form an optically active epoxy-aryl ether.
 35. Themethod of claim 26 wherein the active methylene compound is a diester ora half-ester thereof.
 36. The method of claim 26 wherein the activemethylene compound is a dialkyl malonate.
 37. The method of claim 26wherein the lactone contains a carboxyalkoxy substituent.
 38. The methodof claim 37 wherein the carboxyalkoxy group undergoes hydrolysis anddecarboxylation.
 39. The method of claim 26 further comprising reducingthe lactone to provide a hydroxy-substituted tetrahydrofuran.
 40. Themethod of claim 38 further comprising reducing the lactone to provide ahydroxy-substituted tetrahydrofuran.
 41. The method of claim 39 furthercomprising activating the hydroxy group of the hydroxy-substitutedtetrahydrofuran and substituting the activated tetrahydrofuran position.42. The method of claim 44 wherein the tetrahydrofuran position issubstituted with a nucleophilic compound.
 43. The method of claim 41wherein the tetrahydrofuran position is substituted with a 1-alkynylcompound.
 44. The method of any one of claims 41 through 43 wherein thesubstitution produces an enantiomeric excess of a stereoisomer.
 45. Themethod of claim 44 wherein the substitution produces a steroisomer thatis present in at least about 60 percent relative to the othersteroisomer.
 46. The method of claim 44 wherein the substitutionproduces a steroisomer that is present in at least about 70 percentrelative to the other steroisomer.
 47. The method of claim 44 whereinthe substitution produces a trans steoroisomer that is present in atleast about 60 percent relative to the cis steroisomer.
 48. The methodof claim 44 wherein the substitution produces a trans steoroisomer thatis present in at least about 70 percent relative to the cis steroisomer.49. The method of claim 44 wherein the substitution produces a cissteoroisomer that is present in at least about 60 percent relative tothe trans steroisomer.
 50. The method of claim 44 wherein thesubstitution produces a cis steoroisomer that is present in at leastabout 70 percent relative to the trans steroisomer.
 51. The method ofclaim of claim 39 wherein the hydroxy-substituted tetrahydrofuran isrepresented by the following formula:

wherein Ar is optionally substituted carbocyclic aryl or heteroaryl. 52.The method of claim 51 wherein Ar is optionally substituted carbocyclicaryl.
 53. The method of claim 51 wherein Ar is optionally substitutedphenyl.